Biomedicine & Pharmacotherapy 90 (2017) 24–37
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Review
Current FDA-approved treatments for non-small cell lung cancer and potential biomarkers for its detection Karla A. Ruiz-Cejaa , Yolanda I. Chirinob,* a
Licenciatura en Biología, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, CP 54059, Estado de México, Mexico Laboratorio de Carcinogénesis y Toxicología, Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, CP 54059, Estado de México, Mexico b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 4 January 2017 Received in revised form 21 February 2017 Accepted 7 March 2017
Background: Lung cancer is the leading worldwide cancer with almost 1.5 million deaths every year. Some drugs for lung cancer treatment have been available on the market for decades, but novel drugs have emerged promising better outcomes, especially for Non-Small Cell Lung Cancer (NSCLC), which represents 75% of lung cancer cases. However, how much do drugs have evolved for NSCLC treatment? Are they sharing the same mechanism of action? Aim: In this review we analyzed how the approved drugs by Federal Drug Agency for NSCLC have advanced in the last four decades identifying shared mechanism of action of medicines against NSCLC treatment and some of the potential biomarkers for early detection. Results: Cisplatin and its derivatives are still the most used therapy in combination with some other more specific drugs. However, increasing the survival rates seems to be a great challenge and research is moving into early detection through biomarkers but also trying to identify molecules such as those derived from the immune system, cell-free DNA, non-coding RNAs, but also polymorphisms to detect early tumor formation. Conclusions: Cisplatin and derivatives have been one of the most successful therapies in spite of their side effects and low specificity. Some of the drugs developed after cisplatin discovery, have been targeted the epidermal growth factor receptor, anaplastic lymphoma kinase, programmed cell death 1 ligand and vascular endothelial growth factor. Since none of the pharmacological treatments in combination with radiation/surgery have extended dramatically the survival rate, research is now focused in early cancer detection in combination with precision medicine, which attempts to treat patients individually according to their stage and tumor characteristics. © 2017 Elsevier Masson SAS. All rights reserved.
Keywords: Non-small cell lung cancer Lung cancer treatment Federal drug agency Biomarkers
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . FDA approved treatments for non-small cell lung cancer since 80’s decade 2.1. Platinum drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cisplatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. First-line treatment for lung adenocarcinoma . . . . . . . . . . . . . . . . . 2.2. Crizotinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Atezolizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. 2.2.3. Pembrolizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pemetrexed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.4. Bevacizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.5. Second-line treatment for lung adenocarcinoma . . . . . . . . . . . . . . . 2.3. 2.3.1. Ceritinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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* Corresponding author at: Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Av. de Los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Estado de México, Mexico. E-mail address: [email protected] (Y.I. Chirino). http://dx.doi.org/10.1016/j.biopha.2017.03.018 0753-3322/© 2017 Elsevier Masson SAS. All rights reserved.
K.A. Ruiz-Ceja, Y.I. Chirino / Biomedicine & Pharmacotherapy 90 (2017) 24–37
2.3.2. Alectinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . First-line treatment for squamous cell carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Paclitaxel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.1. Methotrexate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.2. Second-line treatment for squamous cell carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Afatinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.1. Necitumumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.2. Nivolumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.3. 2.6. Unspecific treatments used as first-line treatments for both, adenocarcinoma and squamous cell carcinoma . . Gefitinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.1. Vinorelbine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.2. 2.6.3. Gemcitabine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Unspecific treatments used as second-line treatments for both, adenocarcinoma and squamous cell carcinoma 2.7. Ramucirumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7.1. Docetaxel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7.2. 2.7.3. Erlotinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Osimertinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7.4. Early detection through biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Protein biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. 3.2. Biomarkers derived from immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tumor infiltrating lymphocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. C4d complement split product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Autoantibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3. 3.3. Circulating tumor cells (CTCs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cell-free DNA (cfDNA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. miRNAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Polymorphisms and gene copy number . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Final remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.
3.
4. 5.
1. Introduction Lung cancer is the first leading cause of mortality with almost 1.5 million deaths, and represents nearly 1/5 of all cancer deaths according to the World Health Organization (WHO) (World Health Organization, 2012; [1]. Lung cancer is the first cause of mortality for men (23.6%) and the second cause of death for women (13.8%). Lung tumor formation is a complex cell process that involves genetic, epigenetic and environmental factors. Genes that regulate growth, differentiation and apoptosis are frequently involved in tumor development, invasion and metastasis. Histological characterization of tissue developing lung cancer is the most used basis for lung cancer classification (World Health Organization, 2012; National Cancer Institute, 2016; [2] (Fig. 1). Lung cancer can be asymptomatic, but sometimes some signs can appear including persistent cough, trouble breathing, wheezing, blood in sputum, hoarseness, loss of appetite, weight loss, and dysphagia (National Cancer Institute, 2016). According to the National Cancer Institute (2016), there are different procedures for detection, diagnostic and establishment of lung cancer stage and therefore, treatments according to each stage (Fig. 2). Some diagnostic methods include physical exams such as pulmonary function test (PFT) and laboratory tests in blood, urine, sputum cytology or biopsies derived from lung tissue or bone marrow. Imaging studies are also usual through X-ray, magnetic resonance imaging and positron emission tomography scan. Radionuclide bone scan, endoscopic ultrasound, mediastinoscopy, and anterior mediastinotomy are also part of the diagnosis platform (National Cancer Institute, 2015). Moreover, the International Association for the Study of Lung Cancer European Thoracic Oncology Platform multidisciplinary workshop recommended the implementation of epidermal growth factor receptor (EGFR) mutations for NSCLC diagnosed patients [3]. Nevertheless, the mutations in genes encoding
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downstream mitogen-activated protein kinases (MAPK), phosphatidylinositol 3-kinases (PI3K) signaling pathways, anaplastic lymphoma kinase (ALK)-tyrosine kinase receptor, monoclonal antibody against vascular endothelial growth factor receptor 2 (VEGFR-2), KRAS mutations, B-Raf (BRAF), Kirsten rat sarcoma 2 viral oncogene homolog (KRAS), mesenchymal-epithelial transition factor (MET) and human epidermal growth factor receptor 2 (HER2) are also involved in the NSCLC pathogenesis [4,5]. The determination of lung cancer stage is based on whether the cancer is located or has been spread, so the treatment intend to be particular according to the lung cancer stage and mutations (Fig. 3). Despite the advanced methods for diagnosis and even if some of the common genetic abnormalities have been identified, the therapy field is still working on the development of more efficient treatments. In this regard, cisplatin, a drug used since 70's decade, has been one of the most successful drug discovery against cancer, and still the most common chemotherapeutic agent used in combination with other drugs. Cisplatin was approved by the Food and Drug Administration (FDA) as chemotherapeutic agent in 1978 and since then, novel molecules have been approved and are currently used against NSCLC. However, how different are these novel treatments compared with the former molecules? Interestingly, cisplatin remains as the simplest synthetic molecule used as chemotherapeutic agent, and platinum-core derivatives evolved in the following decades having less side effects. The technology advancement then, led to a key discoveries including the role of hormones and mutations in the tumor development, which in turn, brought new molecules for against cancer. In 2004, bevacizumab was one of the first antibody-based therapies, initially used against metastatic colorectal cancer and indeed, the most recent treatments against NSCLC belongs to humanized antibodies (Fig. 4). In this review, we describe the approved drugs
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Fig. 1. Lung cancer is classified into two types of cancer according to the size of the cells: Small cell lung cancer and Non-small cell lung cancer (NSCLC). NSCLC is divided into three types of cancer: Squamous cell carcinoma, Adenocarcinoma and Large cell carcinoma. The most common mutations for adenocarcinoma are shown. AKT1, serinethreonine protein kinase 1; BRAF, B-Raf proto-oncogene, serine/threonine kinase; EGFR, epidermal growth factor receptor; KRAS, KRAS proto-oncogene; MET, MET protooncogene; RET, ret proto-oncogene; ALK, anaplastic lymphoma receptor tyrosine kinase; DDR2, discoidin domain receptor tyrosine kinase 2; HER2, erb-b2 receptor tyrosine kinase 2; MEK1, serine/threonine protein kinase MEK1; NRAS, neuroblastoma RAS viral oncogene homolog; ROS1, ROS proto-oncogene 1; FGFR1, fibroblast growth factor receptor 1; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PTEN, phosphatase and tensin homolog.
Fig. 2. Description of different therapies used for the treatment of lung cancer.
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Fig. 3. Description of different therapies against cancer according to the stage of tumor.
used against NSCLC by the FDA according to the cancer.gov website. We analyzed the mechanism of action and resistance of medicines used late 70’s decade to the present and grouping them in two main categories, a) drugs uses for adenocarcinoma and b) squamous cell carcinoma (Fig. 5). In addition, we identified some novel strategies that are under development and we analyze why some of them still have to face some challenges. 2. FDA approved treatments for non-small cell lung cancer since 80’s decade In spite of being an unspecific treatment used in adenocarcinoma and squamous cell carcinoma, cisplatin and its derivatives are used as the first-line treatment in combination with other drugs and/or radiotherapy.
2.1. Platinum drugs 2.1.1. Cisplatin Cis-diamminedichloroplatinum (Cisplatin) was approved by the FDA in 1978. However, nephrotoxicity, ototoxicity, and neurotoxicity (Hall et al.) are the main side effects that have led to analogues with less side effects such as carboplatin (cyclobutane-1,1-dicarboxylato platinum(II); Carboplatin) which was approved by the FDA in 1989. Platinum drugs uses organic cation transporter 2 (OCT-2) as uptake mechanism [6] and then form adducts with DNA triggering oxidative stress, DNA damage and apoptosis, which unfortunately have the same effects in tissues that expresses OCT transporters, for instance, in kidney leading to nephrotoxicity [7]. Cisplatin and derivatives acquire resistance by several mechanisms, including a reduction in the cell uptake but also the overexpression of the copper-transporting P-type adenosine triphosphatase in patients with oral squamous cell carcinoma
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Fig. 4. Evolution of the drugs used in the treatment of NSCLC from 1978 to 2016. After 70’s decade, the use of cisplatin-derivatives was developed in order to decrease the side effects of cisplatin. Later, specific molecules designed for specific cell targets were developed in the becoming decades, and the use of antibodies as treatments was recently developed.
Fig. 5. FDA approved drugs for lung cancer treatment according to histological subtypes and the main mutations are indicated.
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had lower response to cisplatin treatment and unfavorable clinical outcome [8–10]. The overexpression of these transporters is involved in the resistance of several tumors such as breast, gastric, hepatic [11–13], among others, but it has not been described in lung cancer yet. Somatic mtDNA mutations such as MTND4, which encodes the subunit of NADH ubiquinone oxidoreductase, was been detected in a patient with ovarian carcinoma and treated with cisplatin suggesting the involvement of mtDNA mutations in the resistance effect [14], but some other cellular events including alteration in miRNAs such as MiR-192, have been identified as key modulator of sensitivity against cisplatin treatment [15]. However, these last two alterations have not been described in NSCLC patients treated with cisplatin but could be involved in resistance against cisplatin therapy. 2.2. First-line treatment for lung adenocarcinoma 2.2.1. Crizotinib (R)-3-[1-(2,6Dichloro-3-fluorophenyl) ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine (Crizotinib) was approved by the FDA in 2011. Pharmacology: Crizotinib is an oral small-molecule tyrosine kinase inhibitor targeting ALK, MET, and ROS1 tyrosine kinases [16]. ALK is a receptor tyrosine kinase normally expressed in discrete regions of the developing nervous system. Resistance can be acquired when mutations on the TK domains reduce the activity of TKIs and therefore modify the binding kinetics of the target molecule. The mutation can activate another signaling pathway, thus eliminating signal passage through the stage originally inhibited by the drug [17]. The treatment with crizotinib is used as first-line treatment of ALKrearranges at stage IV of NSCLC (According to American Cancer Society, 2016). 2.2.2. Atezolizumab Human IgG1 monoclonal anti-PD-L1 antibody (Atezolizumab) was approved by the FDA in 2016. Pharmacology: Atezolizumab inhibits the interaction between PD-L1–PD-1 and PD-L1–B7.1, allowing T cells to perform their antitumor function and increasing T-cell priming [18]. It avoids Fc-effector function by binding to Fc receptors, removing the cytotoxicity of antibody-dependent cells and decreasing anticancer immunity [19]. The Fc domain is part of the antibody and it controls effector functions, for instance, antibody-dependent cell-mediated cytotoxicity (ADCC) by binding to the Fc receptor on effector cells (cited in [20]) and resistance has not been reported yet. Atezolizumab can be used as a second or third –line treatment after failed therapies of NSCLC [19]. 2.2.3. Pembrolizumab Monoclonal highly selective IgG4 antibody (Pembrolizumab) was approved by the FDA in 2016. Pharmacology: Pembrolizumab targets PD-1 receptor and inhibits PD-1 binding to PD-L1 and PDL2 and therefore, the inhibitory signals in T-cells are avoided [21,22]. Even though pembrolizumab is a novel treatment, some adverse drug reactions have been reported in clinical trials, such as diarrhea, pneumonia, fatigue and decreased appetite [22] but resistance has not been reported yet [23]. Pembrolizumab is used as second-line treatment in patients with advanced NSCLC and with tumors that express PD-L1, which previous treatments failed. 2.2.4. Pemetrexed N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H 395 pyrrolo [2,3-d] pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt (Pemetrexed) was approved by the FDA in 2004. Pharmacology: Pemetrexed is a multi-target synthetic anti-folate drug that competes with reduced folate for binding sites, disrupting the activity of several
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enzymes including dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyltansferase (GARFT) and thymidylate synthase (TS) [24]. It enters into the cell through the reduced folate carrier and inhibits the synthesis of purine and pyrimidine from multiple channels preventing cell replication [25]. A decreased expression of the reduced folate carrier [26], a reduced rate of polyglutamation [27], and an increased activity of glutamyltransferase [28], may lead to an acquired resistance. Pemetrexed is used as first-line treatment in combination with cisplatin at stage IV (According to American Cancer Society, 2016) or as second-line treatment after chemotherapy. 2.2.5. Bevacizumab Antivascular endothelial growth factor monoclonal antibody (Bevacizumab) was approved by the FDA in 2006. Pharmacology: Bevacizumab binds to the vascular endothelial growth factor (VEGF) receptor inhibitors (Flt-1 and KDR) in order to prevent endothelial cell proliferation and angiogenesis [25]. Its mechanism of resistance is associated with anti-VEGF treatment, but it is not completely understood [29]. Bevacizumab is used as the first-line treatment with carboplatin at stage IV of NSCLC [30]. 2.3. Second-line treatment for lung adenocarcinoma 2.3.1. Ceritinib 5-Chloro-N4- [2-[(1 methylethyl) sulfonyl] phenyl] N2- [5methyl- 2-(1-methylethoxy)- 4-(4 piperidinyl) phenyl] 2,4pyrimidinediamine (Ceritinib) was approved by the FDA in 2014. Pharmacology: Ceritinib is an ATP-competitive, tyrosine kinase inhibitor of ALK that inhibits the insulin-like growth factor 1 (IGF-1) receptor [31] and insulin receptor (INSR). It has been reported that ceritinib is more potent than crizotinib against ALK, but it does not inhibit the kinase activity of MET. Although ceritinib is a novel drug, acquired resistance has been already detected. Ceritinib is a second-generation kinase inhibitor and it can overcome crizotinib-resistant mutations [32]. It is used as a second-line treatment in patients with ALK-rearranged at stage IV of NSCLC resistant to or crizotinib intolerant [30]. 2.3.2. Alectinib 9-ethyl-6, 6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride (Alectinib) was approved by the FDA in 2015. Pharmacology: Alectinib is a second generation and highly selective ALK and RET inhibitor [33] [34]. Alectinib can induce apoptosis by activating caspase-3/7 and inhibiting ALK inducing tumor regression. In addition, it is effective against EML4-ALK tumors, which are tumors with a fusion of the anaplastic lymphoma kinase (ALK) with the echinoderm microtubule-associated protein-like 4 (EML4) in NSCLC. The resistance against alectinib treatment has not been reported yet but the therapy with heat shock protein 90 (Hsp90) inhibitors could trigger alectinib resistance [35]. It used as first-line or second-line treatment of patients with ALK positive or metastatic NSCLC where crizotinib treatment failed [33]. 2.4. First-line treatment for squamous cell carcinoma 2.4.1. Paclitaxel 5b, 20-epoxy-1,2a,4,7b,10b,13a-hexahydroxytax 11-en-9one 4,10-diacetate 2-benzoate 13-ester in combination with (2R,3S)-N-benzoyl-3-phenylisoserine (Paclitaxel) was approved by the FDA in 2012. Pharmacology: Paclitaxel is a microtubule inhibitor that binds to b-tubulin inducing the formation of stable bundles of microtubules and preventing depolymerization. It interferes with the normal function of cellular microtubules [36] and leads to mitotic arrest and cell death. Tumor cells resistance is
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associated with overexpression of the efflux transporter P-glycoprotein [36–38]. P-glycoprotein is encoded by MDR1 gene; it is a pump that effluxes out the drug from cells reducing intracellular drug accumulation [38]. It is used as first-line treatment in patients with squamous cells at stage IV or after a failure of combination chemotherapy for metastatic disease or relapse within six months of adjuvant chemotherapy (According to American Cancer Society, 2016). 2.4.2. Methotrexate N-[4-[[(2,4-diamino-6-pteridinyl) methyl] methylamino] benzoyl]-L glutamic acid (Methotrexate) was approved by FDA in 2014. Pharmacology: Methotrexate inhibits dihydrofolate reductase (DHFR) causing the disruption of cellular folate metabolism, suppresses synthesis of purine and pyrimidine and inhibits the proliferation of cells in the late G1 phase [39]. Rhee et al. described five different resistance mechanisms of the methotrexate treatment: 1) less accumulation due to impaired transport; 2) decreased retention caused by a lack of polyglutamate formation; 3) an increase in DHFR; 4) a mutated DHFR that binds methotrexate less avidly than the normal enzyme and, 5) an increased level of g-glutamyl hydrolase that hydrolyses methotrexate polyglutamates [40]. Methotrexate is used alone or in combination with other anticancer agents in the treatment of lung cancer, particularly squamous cell and small cell types. 2.5. Second-line treatment for squamous cell carcinoma 2.5.1. Afatinib 2-butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino] 7[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-,(2E)-,(2Z)-2 butenedioate (1:2) (Afatinib) was approved by the FDA in 2013. Pharmacology: Afatinib is an ATP-competitive molecule derivative of the aniline-quinazoline that inhibits cysteine. It blocks the downstream signaling from ErbB family dimers and human epidermal growth factor receptor 2 (HER2/ ErbB2) [41,42]. Currently, there is no extensive clinical data describing afatinib resistance [43]. However, in vitro studies indicate that the activation of EGFR-dependent downstream pathways, including PI3K/AKT and MAPK/ERK, could cause resistance to afatinib [44]. This drug is used as an antitumor therapeutic for overcoming drug resistance to the first generation EGFR TKIs by covalently binding to cysteine residues within the catalytic domain. It is also used as first-line treatment in stage IV of EGFR-mutant NSCLC [30]. 2.5.2. Necitumumab Second generation human IG1 EGFR monoclonal antibody (Necitumumab) was approved by the FDA in 2015. Pharmacology: It inhibits the activity of EGFR, preventing the activation of the receptor and the downstream signaling [45]. Necitumumab blocks the domain III binding site of EGFR receptor in order to prevent its activation and the activation of MAP kinases [46]. No acquired resistance information has been reported yet. It is used in combination with gemcitabine and cisplatin chemotherapy as first-line treatment in patients with advanced squamous nonsmall-cell lung cancer [45]. 2.5.3. Nivolumab Human IgG4 PD-1 monoclonal antibody (Nivolumab) was approved by FDA in 2015. The IgG4 isotype acts as antibodydependent cellular cytotoxicity (ADCC). Nivolumab binds Programmed Death 1 (PD-1), blocks Programmed cell Death 1 Ligand 1 (PD-L1) and PD-L2 binding and binds to the PD-1 receptor [47]. In NSCLC, PD-1 is overexpressed in cancer cells inducing apoptosis of T cells, which has as a consequence the tumor growth [48]. Studies
reporting resistance to PD-1 blocking are limited. However, upregulation of alternative immune checkpoints such as TIM-3 in a mice model with lung adenocarcinoma, had an adaptive resistance to the PD-1 blockade [23]. Nivolumab is used after platinum-based chemotherapy or alternative first-line agents for patients at stage III or IV of NSCLC [49]. 2.6. Unspecific treatments used as first-line treatments for both, adenocarcinoma and squamous cell carcinoma 2.6.1. Gefitinib N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3–4-morpholin) propoxy] (Gefitinib) was approved by the FDA in 2003. Pharmacology: It is a selective Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (EGFR-TKI) that competes for the ATP binding sites blocking EGFR activation in patients with somatic mutations in EGFR such as L858R and exon 19 deletions [50,51]. EGFR TKIs inhibit receptor phosphorylation, tumor cell adhesion and invasion, and growth of tumor cells [52]. One of the most common acquired resistances of Gefitinib is the T790 M mutation [53], which determines the affinity of ATP-competitive EGFR-TK inhibitors to EGFR-TK. Other mechanisms responsible for acquired resistance to EGFR TKIs are MET amplification, epithelial-tomesenchymal transition (EMT) signature, histologic transformation to small cell lung cancer, and AXL kinase activation [54]. AXL is a tyrosine kinase receptor that promotes cell proliferation, migration, and invasion in cancer. The activation of AXL signaling pathway may confer TKI resistance in EGFR. It is used in patients with EGFR mutations at stage IV as a first-line treatment (According to American Cancer Society, 2016), or as a secondline treatment after failure of platinum-based or docetaxel chemotherapies. 2.6.2. Vinorelbine 30 ,40 -didehydro-40 -deoxy-C0 -norvincaleukoblastine [R-(R*,R*)2,3-dihydroxybutanedioate (1:2)] (Vinorelbine) was approved by the FDA in 1994. Pharmacology: It is an alkaloid compound that disrupts the formation of microtubule assemblies during mitosis. It binds the b-tubulin subunit leading to mitotic arrest and cell death [55–57]. Vinorelbine also disrupts metabolism of amino acid, cyclic AMP, glutathione, nucleic acids and lipid biosynthesis [58]. The sensitivity of cancer cells to vinorelbine has been associated with the expression of MDR1, Pgp, MRP-1, RLIP76, RAF1 genes, and the activation of AKT/ERK proteins [55,59]. It is used as a single treatment or in combination with cisplatin for NSCLC at stage III and as a monotherapy for previously treated patients [60,30]. 2.6.3. Gemcitabine 20 -deoxy-20 ,20 -difluorocytidine monohydrochloride (b-isomer; Gemcitabine) was approved by FDA in 1996. Pharmacology: Gemcitabine inhibits processes required for DNA synthesis. The incorporation of gemcitabine triphosphate (dFdCTP) into DNA replication is the major mechanism by which gemcitabine causes cell death. After incorporation of gemcitabine nucleotide on the end of the elongating DNA strand, one more deoxynucleotide is added, and therefore, DNA polymerases are unable to proceed. It stops normal development and cell division by ribonucleotide reductase inhibition [61]. Lung cancer cells become resistant to gemcitabine due to decreased dCDA activity [62], the activation of NF-kB via and the subsequent overexpression of Bfl-1 [63]. Bfl-1 is a transcriptional target of NF-kB. It interacts and isolates proapoptotic molecules, suppressing apoptosis and inhibiting cytochrome c release from mitochondria [64,65]. Gemcitabine is indicated in combination with cisplatin for the first-line treatment of patients with stage IIIA, IIIB or IV [30,66].
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2.7. Unspecific treatments used as second-line treatments for both, adenocarcinoma and squamous cell carcinoma 2.7.1. Ramucirumab Recombinant human IgG1 monoclonal antibody (Ramucirumab) was approved by the FDA in 2014. Ramucirumab binds to VEGFR-2 and blocks the binding of the VEGF ligand to VEGFR-2, controlling the proliferation and migration of cells [67]. Resistance for ramucirumab has not been reported. Ramucirumab is used with docetaxel for NSCLC with disease progression on or after platinum-based chemotherapy. It is used as a second-line treatment alone or in combination with docetaxel in patients at stage IV of NSCLC after platinum-based therapy [68]. 2.7.2. Docetaxel (2R,3S)-N-carboxy-3-phenylisoserine, N-tert-butyl ester, 13ester with 5b-20-epoxy-1,2a,4,7b,10b,13a-hexahydroxytax-11en-9-one 4-acetate 2-benzoate, trihydrate (Docetaxel) was approved by the FDA in 1999. Pharmacology: It is an antineoplastic agent that belongs to taxane family and inhibits microtubule depolymerization leading the metaphase to anaphase transition arrest and subsequently causing apoptosis [69]. Acquired resistance is related to alterations in the docetaxel metabolism, drug transporters, and deregulation of the cell cycle and apoptosis pathways [70]. However, mutations that abrogate drug binding have been also reported and alterations in microtubule- gene expression and signaling [71]. Docetaxel is used as second line therapy for stage IIIA, IIIB or IV after platinum therapy failure and it can be used in combination with cisplatin [30]. 2.7.3. Erlotinib N-(3-ethynylphenyl)-6,7 bis(2-methoxyethoxy)-4-quinazolinamine (Erlotinib) and was approved by the FDA in 2004. Pharmacology: Erlotinib is small TKI molecule that target EGFR. It binds to the intracellular TK domain of EGFR and blocks its ATPbinding site [72]. Erlotinib acquired resistance is linked to the secondary mutation T790 M [53], MET activation and the methylation of death-associated protein kinase (DAPK). MET is a proto-oncogene that encodes the receptor for the hepatocyte growth factor (HGF) and is associated with promoting cell invasion and metastasis [73]. DAPK is a hypermethylated protein kinase that causes erlotinib resistance [74]. Erlotinib drug is used in stage III or IV as a first-line treatment for NSCLC in patients where EGFR exon 19 deletions or exon 21 substitution mutations are present. Thus, it is used as second- and third-line treatment in patients with EGFR wild-type NSCLC after failed chemotherapy [75,30,76] and in combination with gemcitabine. On October 2016, FDA restricted the use of erlotinib for patients with specific EGFR mutations. 2.7.4. Osimertinib N-(2-{2dimethylaminoethyl-methylamino}-4-methoxy-5-{[4(1-methylindol-3-yl)pyrimidin-2yl]amino}phenyl)prop-2-enamide mesylate salt. (Osimertinib) was approved by the FDA in 2015. Pharmacology: Osimertinib is a kinase inhibitor of EGFR, which binds to EGFR with the following mutations: T790 M, L858R, and exon 19 deletion, over the wild-type form of EGFR [77]. It is a thirdgeneration drug that can deregulate DNA synthesis and proliferation [78]. It is used in patients with EGFR T790 M whose disease has progressed after a first-line TKI treatment [78,79]. 3. Early detection through biomarkers Despite of the evolution of drugs approved for NSCLC treatment, it seems that cisplatin has been one of the most successful molecules discovered that is now combined with some other more specific treatments. However, in the last decade the
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cancer research has moved into the search for early diagnosis using biomarkers, partially, because none of the treatments, alone or in combination are completely effective. By definition, a good biomarker should be a molecule generated exclusively by cancer cells and/or by the tumor microenvironment in sufficient amount to be properly detected in an early stage of the tumor development [80]. Biomarkers can be useful not only for diagnosis but also for prognostic and as a predictive tool for treatment response. The nature of the biomarkers is wide and includes proteins derived from tumors or proteins derived from immune system, but also some other molecules as DNA and miRNAs and polymorphisms and alterations in the gene copy number. Below, a brief description of some of the most promising biomarkers that are being or could be used for early diagnosis. 3.1. Protein biomarkers Classical protein-based circulating biomarkers for various solid tumors have been studied in the last decades including carcinoembryonic antigen (CEA), CYFRA21-1, plasma kallikrein B1 (KLKB1) and neuron-specific enolase [30]. However, specificity is the main inconvenient for lung cancer diagnosis [81]. For instance, CEA was suggested around 2004 to be a biomarker for detection of advanced NSCLC. Patients with levels above 50 ng/mL are considered as positive for this type of cancer and unfortunately is also a poor prognosis biomarker [82]. Lately, was also suggested as biomarker for gastric cancer detection in combination with cancer antigen 19-9 and cancer antigen 72-4 [83]. Until now, there is no specific protein biomarker which could establish the stage of the lung cancer and moreover, more than one biomarker is needed for a more precise diagnosis. The simultaneous detection of at least two proteins is also promising and detection of CEA and CYFRA211 in human serum using quantum dot-doped polystyrene nanoparticles could be used for lung cancer patients [84]. The serum peptidome has been identified using a ZipTip technology with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, identifying C3 and fibrinogen a chain as peptides, specifically derived from NSCLC patients [85]. Thus, new potential biomarkers including KDM1A, a histone demethylase for H3K4me2/me1 demethylation has been proposed as a therapeutic agent against NSCLC, specifically, related to metastasis prediction [86]. 3.2. Biomarkers derived from immune system Immunotherapy is the involvement of immune-mediated therapies designated to destroy tumor cells and in the last decade, specific characteristics of immune cells nested in tumors have been suggested not only as biomarkers but also as therapy. 3.2.1. Tumor infiltrating lymphocytes The microenvironment of a tumor is mainly composed by endothelial cells, fibroblast, and immune cells and particularly, lymphocytes can be detected in different quantities among different types of tumors but also among patients with the same type of cancer. Tumor-infiltrating lymphocytes (TILs) is a complex mixture of immune cells which besides lymphocytes T and B includes also macrophages, natural killer cells and dendritic cells. Specifically, TILs could predict the prognosis in different tumors based on specific antitumor activity of CD4(+) and CD8(+) T cells. For instance, triple-negative breast cancer patients with high population of TILs had better survival than patients with lower TILs cells [87]. More recently, some specific adhesion molecules such as CD103, which kill tumor cells through immune checkpoint receptor PD-1, have been found in TILs of NSCLC patients and have been associated with favorable clinical outcome [88].
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However, there are some issues regarding to the methodology for quantification that are being addressing. For instance, the International TILs Working Group (formed by 32 experts in TILs research) has established that TILs should be analyzed in the stroma within the borders of the invasive tumor excluding TILs outside of the tumor border and dendritic cells and macrophages [89]. In addition, immunohistochemistry with gene expression analysis seems to offer more accuracy for detection than flow cytometry [90]. For NSCLC, TILs subtyped as CD3(+),CD4(+) and CD8(+) have shown the most robustness for prognostics in patients according with a meta-analysis derived from 7006 patients belonging to 24 different studies performed between 2003 and 2015 [91]. In addition, the antitumor effects of TILs have suggested their potential usage as therapeutic strategy. Currently, TILs have been isolating from patients and then, same patient receives the infusion with isolated TILs for melanoma treatment. This research is approved by the National Cancer Institute in USA (Trial IDs: 2643.00, NCI-2013-00486, NCT01807182, Trial IDs: 13-C-0093, NCI-2013-01586, 130093, P131209, NCT01814046) and it is also used against NSCLC that is metastatic or cannot be removed by surgery (Trial IDs: 14-C-0104, NCI-2014-02481, P131510, NCT02133196). 3.2.2. C4d complement split product Immune activation may generate host-derived markers that are more homogeneous than cancer-derived markers. Immune responses against intracellular and surface tumor antigens have been described in lung cancer patients. Lung tumors activate the classical complement pathway and generate C4d, which is a degradation product of this pathway and can be used for diagnosis and prognosis of lung cancer [92]. 3.2.3. Autoantibodies Cancer patients produce autoantibodies to tumor proteins that are expressed abnormally. The autoantibody test detects early stages of lung cancer and has worked effectively on a large number of individuals from a routine clinical practice setting [93]. 3.3. Circulating tumor cells (CTCs) As a result of constant tumor-cell growth and death, solid tumors release substantial amounts of material into the bloodstream, including circulating tumor cells (CTCs) [30]. CTCs can be sampled in peripheral blood, and they are considered a noninvasive alternative to tissue biopsies for diagnosis of lung cancers [94] using cytokeratins (CK), TTF-1, CD56 and VEGFR2 as CTCs markers, normally detected as different sub-populations [95]. CTCs could be more sensitive for early diagnosis of lung cancer than blood serum markers such as cyfra21-1 or CEA [96]. EGFR mutations, ALK-rearranged pattern, and ROS1 rearrangement have been identified in CTCs from metastatic NSCLC [30]. Understanding metastasis-initiating capabilities of CTCs from primary lung cancer will provide specific adjuvant therapies targeting CTCs to reduce metastasis and improve survival [96]. The quantitation of these cells can yield prognostic information that could be related to tumor biology or burden. One counting method is the CellSearch1 (https://www.cellsearchctc.com/), and is FDA-approved for monitoring patients with advanced-stage cancer. CTCs can be characterized at molecular level, to identify the origin and to obtain biological information about the tumor. Detection of 50CTCs/ 7.5 ml of blood before chemotherapy was associated with an unfavorable clinical outcome compared to patients with
Available online at
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Review
Current FDA-approved treatments for non-small cell lung cancer and potential biomarkers for its detection Karla A. Ruiz-Cejaa , Yolanda I. Chirinob,* a
Licenciatura en Biología, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, CP 54059, Estado de México, Mexico Laboratorio de Carcinogénesis y Toxicología, Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, CP 54059, Estado de México, Mexico b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 4 January 2017 Received in revised form 21 February 2017 Accepted 7 March 2017
Background: Lung cancer is the leading worldwide cancer with almost 1.5 million deaths every year. Some drugs for lung cancer treatment have been available on the market for decades, but novel drugs have emerged promising better outcomes, especially for Non-Small Cell Lung Cancer (NSCLC), which represents 75% of lung cancer cases. However, how much do drugs have evolved for NSCLC treatment? Are they sharing the same mechanism of action? Aim: In this review we analyzed how the approved drugs by Federal Drug Agency for NSCLC have advanced in the last four decades identifying shared mechanism of action of medicines against NSCLC treatment and some of the potential biomarkers for early detection. Results: Cisplatin and its derivatives are still the most used therapy in combination with some other more specific drugs. However, increasing the survival rates seems to be a great challenge and research is moving into early detection through biomarkers but also trying to identify molecules such as those derived from the immune system, cell-free DNA, non-coding RNAs, but also polymorphisms to detect early tumor formation. Conclusions: Cisplatin and derivatives have been one of the most successful therapies in spite of their side effects and low specificity. Some of the drugs developed after cisplatin discovery, have been targeted the epidermal growth factor receptor, anaplastic lymphoma kinase, programmed cell death 1 ligand and vascular endothelial growth factor. Since none of the pharmacological treatments in combination with radiation/surgery have extended dramatically the survival rate, research is now focused in early cancer detection in combination with precision medicine, which attempts to treat patients individually according to their stage and tumor characteristics. © 2017 Elsevier Masson SAS. All rights reserved.
Keywords: Non-small cell lung cancer Lung cancer treatment Federal drug agency Biomarkers
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . FDA approved treatments for non-small cell lung cancer since 80’s decade 2.1. Platinum drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cisplatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. First-line treatment for lung adenocarcinoma . . . . . . . . . . . . . . . . . 2.2. Crizotinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Atezolizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. 2.2.3. Pembrolizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pemetrexed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.4. Bevacizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.5. Second-line treatment for lung adenocarcinoma . . . . . . . . . . . . . . . 2.3. 2.3.1. Ceritinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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* Corresponding author at: Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Av. de Los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Estado de México, Mexico. E-mail address: [email protected] (Y.I. Chirino). http://dx.doi.org/10.1016/j.biopha.2017.03.018 0753-3322/© 2017 Elsevier Masson SAS. All rights reserved.
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2.3.2. Alectinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . First-line treatment for squamous cell carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Paclitaxel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.1. Methotrexate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.2. Second-line treatment for squamous cell carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Afatinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.1. Necitumumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.2. Nivolumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.3. 2.6. Unspecific treatments used as first-line treatments for both, adenocarcinoma and squamous cell carcinoma . . Gefitinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.1. Vinorelbine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.2. 2.6.3. Gemcitabine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Unspecific treatments used as second-line treatments for both, adenocarcinoma and squamous cell carcinoma 2.7. Ramucirumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7.1. Docetaxel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7.2. 2.7.3. Erlotinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Osimertinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7.4. Early detection through biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Protein biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. 3.2. Biomarkers derived from immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tumor infiltrating lymphocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. C4d complement split product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Autoantibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3. 3.3. Circulating tumor cells (CTCs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cell-free DNA (cfDNA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. miRNAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Polymorphisms and gene copy number . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Final remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.
3.
4. 5.
1. Introduction Lung cancer is the first leading cause of mortality with almost 1.5 million deaths, and represents nearly 1/5 of all cancer deaths according to the World Health Organization (WHO) (World Health Organization, 2012; [1]. Lung cancer is the first cause of mortality for men (23.6%) and the second cause of death for women (13.8%). Lung tumor formation is a complex cell process that involves genetic, epigenetic and environmental factors. Genes that regulate growth, differentiation and apoptosis are frequently involved in tumor development, invasion and metastasis. Histological characterization of tissue developing lung cancer is the most used basis for lung cancer classification (World Health Organization, 2012; National Cancer Institute, 2016; [2] (Fig. 1). Lung cancer can be asymptomatic, but sometimes some signs can appear including persistent cough, trouble breathing, wheezing, blood in sputum, hoarseness, loss of appetite, weight loss, and dysphagia (National Cancer Institute, 2016). According to the National Cancer Institute (2016), there are different procedures for detection, diagnostic and establishment of lung cancer stage and therefore, treatments according to each stage (Fig. 2). Some diagnostic methods include physical exams such as pulmonary function test (PFT) and laboratory tests in blood, urine, sputum cytology or biopsies derived from lung tissue or bone marrow. Imaging studies are also usual through X-ray, magnetic resonance imaging and positron emission tomography scan. Radionuclide bone scan, endoscopic ultrasound, mediastinoscopy, and anterior mediastinotomy are also part of the diagnosis platform (National Cancer Institute, 2015). Moreover, the International Association for the Study of Lung Cancer European Thoracic Oncology Platform multidisciplinary workshop recommended the implementation of epidermal growth factor receptor (EGFR) mutations for NSCLC diagnosed patients [3]. Nevertheless, the mutations in genes encoding
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downstream mitogen-activated protein kinases (MAPK), phosphatidylinositol 3-kinases (PI3K) signaling pathways, anaplastic lymphoma kinase (ALK)-tyrosine kinase receptor, monoclonal antibody against vascular endothelial growth factor receptor 2 (VEGFR-2), KRAS mutations, B-Raf (BRAF), Kirsten rat sarcoma 2 viral oncogene homolog (KRAS), mesenchymal-epithelial transition factor (MET) and human epidermal growth factor receptor 2 (HER2) are also involved in the NSCLC pathogenesis [4,5]. The determination of lung cancer stage is based on whether the cancer is located or has been spread, so the treatment intend to be particular according to the lung cancer stage and mutations (Fig. 3). Despite the advanced methods for diagnosis and even if some of the common genetic abnormalities have been identified, the therapy field is still working on the development of more efficient treatments. In this regard, cisplatin, a drug used since 70's decade, has been one of the most successful drug discovery against cancer, and still the most common chemotherapeutic agent used in combination with other drugs. Cisplatin was approved by the Food and Drug Administration (FDA) as chemotherapeutic agent in 1978 and since then, novel molecules have been approved and are currently used against NSCLC. However, how different are these novel treatments compared with the former molecules? Interestingly, cisplatin remains as the simplest synthetic molecule used as chemotherapeutic agent, and platinum-core derivatives evolved in the following decades having less side effects. The technology advancement then, led to a key discoveries including the role of hormones and mutations in the tumor development, which in turn, brought new molecules for against cancer. In 2004, bevacizumab was one of the first antibody-based therapies, initially used against metastatic colorectal cancer and indeed, the most recent treatments against NSCLC belongs to humanized antibodies (Fig. 4). In this review, we describe the approved drugs
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Fig. 1. Lung cancer is classified into two types of cancer according to the size of the cells: Small cell lung cancer and Non-small cell lung cancer (NSCLC). NSCLC is divided into three types of cancer: Squamous cell carcinoma, Adenocarcinoma and Large cell carcinoma. The most common mutations for adenocarcinoma are shown. AKT1, serinethreonine protein kinase 1; BRAF, B-Raf proto-oncogene, serine/threonine kinase; EGFR, epidermal growth factor receptor; KRAS, KRAS proto-oncogene; MET, MET protooncogene; RET, ret proto-oncogene; ALK, anaplastic lymphoma receptor tyrosine kinase; DDR2, discoidin domain receptor tyrosine kinase 2; HER2, erb-b2 receptor tyrosine kinase 2; MEK1, serine/threonine protein kinase MEK1; NRAS, neuroblastoma RAS viral oncogene homolog; ROS1, ROS proto-oncogene 1; FGFR1, fibroblast growth factor receptor 1; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PTEN, phosphatase and tensin homolog.
Fig. 2. Description of different therapies used for the treatment of lung cancer.
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Fig. 3. Description of different therapies against cancer according to the stage of tumor.
used against NSCLC by the FDA according to the cancer.gov website. We analyzed the mechanism of action and resistance of medicines used late 70’s decade to the present and grouping them in two main categories, a) drugs uses for adenocarcinoma and b) squamous cell carcinoma (Fig. 5). In addition, we identified some novel strategies that are under development and we analyze why some of them still have to face some challenges. 2. FDA approved treatments for non-small cell lung cancer since 80’s decade In spite of being an unspecific treatment used in adenocarcinoma and squamous cell carcinoma, cisplatin and its derivatives are used as the first-line treatment in combination with other drugs and/or radiotherapy.
2.1. Platinum drugs 2.1.1. Cisplatin Cis-diamminedichloroplatinum (Cisplatin) was approved by the FDA in 1978. However, nephrotoxicity, ototoxicity, and neurotoxicity (Hall et al.) are the main side effects that have led to analogues with less side effects such as carboplatin (cyclobutane-1,1-dicarboxylato platinum(II); Carboplatin) which was approved by the FDA in 1989. Platinum drugs uses organic cation transporter 2 (OCT-2) as uptake mechanism [6] and then form adducts with DNA triggering oxidative stress, DNA damage and apoptosis, which unfortunately have the same effects in tissues that expresses OCT transporters, for instance, in kidney leading to nephrotoxicity [7]. Cisplatin and derivatives acquire resistance by several mechanisms, including a reduction in the cell uptake but also the overexpression of the copper-transporting P-type adenosine triphosphatase in patients with oral squamous cell carcinoma
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Fig. 4. Evolution of the drugs used in the treatment of NSCLC from 1978 to 2016. After 70’s decade, the use of cisplatin-derivatives was developed in order to decrease the side effects of cisplatin. Later, specific molecules designed for specific cell targets were developed in the becoming decades, and the use of antibodies as treatments was recently developed.
Fig. 5. FDA approved drugs for lung cancer treatment according to histological subtypes and the main mutations are indicated.
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had lower response to cisplatin treatment and unfavorable clinical outcome [8–10]. The overexpression of these transporters is involved in the resistance of several tumors such as breast, gastric, hepatic [11–13], among others, but it has not been described in lung cancer yet. Somatic mtDNA mutations such as MTND4, which encodes the subunit of NADH ubiquinone oxidoreductase, was been detected in a patient with ovarian carcinoma and treated with cisplatin suggesting the involvement of mtDNA mutations in the resistance effect [14], but some other cellular events including alteration in miRNAs such as MiR-192, have been identified as key modulator of sensitivity against cisplatin treatment [15]. However, these last two alterations have not been described in NSCLC patients treated with cisplatin but could be involved in resistance against cisplatin therapy. 2.2. First-line treatment for lung adenocarcinoma 2.2.1. Crizotinib (R)-3-[1-(2,6Dichloro-3-fluorophenyl) ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine (Crizotinib) was approved by the FDA in 2011. Pharmacology: Crizotinib is an oral small-molecule tyrosine kinase inhibitor targeting ALK, MET, and ROS1 tyrosine kinases [16]. ALK is a receptor tyrosine kinase normally expressed in discrete regions of the developing nervous system. Resistance can be acquired when mutations on the TK domains reduce the activity of TKIs and therefore modify the binding kinetics of the target molecule. The mutation can activate another signaling pathway, thus eliminating signal passage through the stage originally inhibited by the drug [17]. The treatment with crizotinib is used as first-line treatment of ALKrearranges at stage IV of NSCLC (According to American Cancer Society, 2016). 2.2.2. Atezolizumab Human IgG1 monoclonal anti-PD-L1 antibody (Atezolizumab) was approved by the FDA in 2016. Pharmacology: Atezolizumab inhibits the interaction between PD-L1–PD-1 and PD-L1–B7.1, allowing T cells to perform their antitumor function and increasing T-cell priming [18]. It avoids Fc-effector function by binding to Fc receptors, removing the cytotoxicity of antibody-dependent cells and decreasing anticancer immunity [19]. The Fc domain is part of the antibody and it controls effector functions, for instance, antibody-dependent cell-mediated cytotoxicity (ADCC) by binding to the Fc receptor on effector cells (cited in [20]) and resistance has not been reported yet. Atezolizumab can be used as a second or third –line treatment after failed therapies of NSCLC [19]. 2.2.3. Pembrolizumab Monoclonal highly selective IgG4 antibody (Pembrolizumab) was approved by the FDA in 2016. Pharmacology: Pembrolizumab targets PD-1 receptor and inhibits PD-1 binding to PD-L1 and PDL2 and therefore, the inhibitory signals in T-cells are avoided [21,22]. Even though pembrolizumab is a novel treatment, some adverse drug reactions have been reported in clinical trials, such as diarrhea, pneumonia, fatigue and decreased appetite [22] but resistance has not been reported yet [23]. Pembrolizumab is used as second-line treatment in patients with advanced NSCLC and with tumors that express PD-L1, which previous treatments failed. 2.2.4. Pemetrexed N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H 395 pyrrolo [2,3-d] pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt (Pemetrexed) was approved by the FDA in 2004. Pharmacology: Pemetrexed is a multi-target synthetic anti-folate drug that competes with reduced folate for binding sites, disrupting the activity of several
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enzymes including dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyltansferase (GARFT) and thymidylate synthase (TS) [24]. It enters into the cell through the reduced folate carrier and inhibits the synthesis of purine and pyrimidine from multiple channels preventing cell replication [25]. A decreased expression of the reduced folate carrier [26], a reduced rate of polyglutamation [27], and an increased activity of glutamyltransferase [28], may lead to an acquired resistance. Pemetrexed is used as first-line treatment in combination with cisplatin at stage IV (According to American Cancer Society, 2016) or as second-line treatment after chemotherapy. 2.2.5. Bevacizumab Antivascular endothelial growth factor monoclonal antibody (Bevacizumab) was approved by the FDA in 2006. Pharmacology: Bevacizumab binds to the vascular endothelial growth factor (VEGF) receptor inhibitors (Flt-1 and KDR) in order to prevent endothelial cell proliferation and angiogenesis [25]. Its mechanism of resistance is associated with anti-VEGF treatment, but it is not completely understood [29]. Bevacizumab is used as the first-line treatment with carboplatin at stage IV of NSCLC [30]. 2.3. Second-line treatment for lung adenocarcinoma 2.3.1. Ceritinib 5-Chloro-N4- [2-[(1 methylethyl) sulfonyl] phenyl] N2- [5methyl- 2-(1-methylethoxy)- 4-(4 piperidinyl) phenyl] 2,4pyrimidinediamine (Ceritinib) was approved by the FDA in 2014. Pharmacology: Ceritinib is an ATP-competitive, tyrosine kinase inhibitor of ALK that inhibits the insulin-like growth factor 1 (IGF-1) receptor [31] and insulin receptor (INSR). It has been reported that ceritinib is more potent than crizotinib against ALK, but it does not inhibit the kinase activity of MET. Although ceritinib is a novel drug, acquired resistance has been already detected. Ceritinib is a second-generation kinase inhibitor and it can overcome crizotinib-resistant mutations [32]. It is used as a second-line treatment in patients with ALK-rearranged at stage IV of NSCLC resistant to or crizotinib intolerant [30]. 2.3.2. Alectinib 9-ethyl-6, 6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride (Alectinib) was approved by the FDA in 2015. Pharmacology: Alectinib is a second generation and highly selective ALK and RET inhibitor [33] [34]. Alectinib can induce apoptosis by activating caspase-3/7 and inhibiting ALK inducing tumor regression. In addition, it is effective against EML4-ALK tumors, which are tumors with a fusion of the anaplastic lymphoma kinase (ALK) with the echinoderm microtubule-associated protein-like 4 (EML4) in NSCLC. The resistance against alectinib treatment has not been reported yet but the therapy with heat shock protein 90 (Hsp90) inhibitors could trigger alectinib resistance [35]. It used as first-line or second-line treatment of patients with ALK positive or metastatic NSCLC where crizotinib treatment failed [33]. 2.4. First-line treatment for squamous cell carcinoma 2.4.1. Paclitaxel 5b, 20-epoxy-1,2a,4,7b,10b,13a-hexahydroxytax 11-en-9one 4,10-diacetate 2-benzoate 13-ester in combination with (2R,3S)-N-benzoyl-3-phenylisoserine (Paclitaxel) was approved by the FDA in 2012. Pharmacology: Paclitaxel is a microtubule inhibitor that binds to b-tubulin inducing the formation of stable bundles of microtubules and preventing depolymerization. It interferes with the normal function of cellular microtubules [36] and leads to mitotic arrest and cell death. Tumor cells resistance is
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associated with overexpression of the efflux transporter P-glycoprotein [36–38]. P-glycoprotein is encoded by MDR1 gene; it is a pump that effluxes out the drug from cells reducing intracellular drug accumulation [38]. It is used as first-line treatment in patients with squamous cells at stage IV or after a failure of combination chemotherapy for metastatic disease or relapse within six months of adjuvant chemotherapy (According to American Cancer Society, 2016). 2.4.2. Methotrexate N-[4-[[(2,4-diamino-6-pteridinyl) methyl] methylamino] benzoyl]-L glutamic acid (Methotrexate) was approved by FDA in 2014. Pharmacology: Methotrexate inhibits dihydrofolate reductase (DHFR) causing the disruption of cellular folate metabolism, suppresses synthesis of purine and pyrimidine and inhibits the proliferation of cells in the late G1 phase [39]. Rhee et al. described five different resistance mechanisms of the methotrexate treatment: 1) less accumulation due to impaired transport; 2) decreased retention caused by a lack of polyglutamate formation; 3) an increase in DHFR; 4) a mutated DHFR that binds methotrexate less avidly than the normal enzyme and, 5) an increased level of g-glutamyl hydrolase that hydrolyses methotrexate polyglutamates [40]. Methotrexate is used alone or in combination with other anticancer agents in the treatment of lung cancer, particularly squamous cell and small cell types. 2.5. Second-line treatment for squamous cell carcinoma 2.5.1. Afatinib 2-butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino] 7[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-,(2E)-,(2Z)-2 butenedioate (1:2) (Afatinib) was approved by the FDA in 2013. Pharmacology: Afatinib is an ATP-competitive molecule derivative of the aniline-quinazoline that inhibits cysteine. It blocks the downstream signaling from ErbB family dimers and human epidermal growth factor receptor 2 (HER2/ ErbB2) [41,42]. Currently, there is no extensive clinical data describing afatinib resistance [43]. However, in vitro studies indicate that the activation of EGFR-dependent downstream pathways, including PI3K/AKT and MAPK/ERK, could cause resistance to afatinib [44]. This drug is used as an antitumor therapeutic for overcoming drug resistance to the first generation EGFR TKIs by covalently binding to cysteine residues within the catalytic domain. It is also used as first-line treatment in stage IV of EGFR-mutant NSCLC [30]. 2.5.2. Necitumumab Second generation human IG1 EGFR monoclonal antibody (Necitumumab) was approved by the FDA in 2015. Pharmacology: It inhibits the activity of EGFR, preventing the activation of the receptor and the downstream signaling [45]. Necitumumab blocks the domain III binding site of EGFR receptor in order to prevent its activation and the activation of MAP kinases [46]. No acquired resistance information has been reported yet. It is used in combination with gemcitabine and cisplatin chemotherapy as first-line treatment in patients with advanced squamous nonsmall-cell lung cancer [45]. 2.5.3. Nivolumab Human IgG4 PD-1 monoclonal antibody (Nivolumab) was approved by FDA in 2015. The IgG4 isotype acts as antibodydependent cellular cytotoxicity (ADCC). Nivolumab binds Programmed Death 1 (PD-1), blocks Programmed cell Death 1 Ligand 1 (PD-L1) and PD-L2 binding and binds to the PD-1 receptor [47]. In NSCLC, PD-1 is overexpressed in cancer cells inducing apoptosis of T cells, which has as a consequence the tumor growth [48]. Studies
reporting resistance to PD-1 blocking are limited. However, upregulation of alternative immune checkpoints such as TIM-3 in a mice model with lung adenocarcinoma, had an adaptive resistance to the PD-1 blockade [23]. Nivolumab is used after platinum-based chemotherapy or alternative first-line agents for patients at stage III or IV of NSCLC [49]. 2.6. Unspecific treatments used as first-line treatments for both, adenocarcinoma and squamous cell carcinoma 2.6.1. Gefitinib N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3–4-morpholin) propoxy] (Gefitinib) was approved by the FDA in 2003. Pharmacology: It is a selective Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (EGFR-TKI) that competes for the ATP binding sites blocking EGFR activation in patients with somatic mutations in EGFR such as L858R and exon 19 deletions [50,51]. EGFR TKIs inhibit receptor phosphorylation, tumor cell adhesion and invasion, and growth of tumor cells [52]. One of the most common acquired resistances of Gefitinib is the T790 M mutation [53], which determines the affinity of ATP-competitive EGFR-TK inhibitors to EGFR-TK. Other mechanisms responsible for acquired resistance to EGFR TKIs are MET amplification, epithelial-tomesenchymal transition (EMT) signature, histologic transformation to small cell lung cancer, and AXL kinase activation [54]. AXL is a tyrosine kinase receptor that promotes cell proliferation, migration, and invasion in cancer. The activation of AXL signaling pathway may confer TKI resistance in EGFR. It is used in patients with EGFR mutations at stage IV as a first-line treatment (According to American Cancer Society, 2016), or as a secondline treatment after failure of platinum-based or docetaxel chemotherapies. 2.6.2. Vinorelbine 30 ,40 -didehydro-40 -deoxy-C0 -norvincaleukoblastine [R-(R*,R*)2,3-dihydroxybutanedioate (1:2)] (Vinorelbine) was approved by the FDA in 1994. Pharmacology: It is an alkaloid compound that disrupts the formation of microtubule assemblies during mitosis. It binds the b-tubulin subunit leading to mitotic arrest and cell death [55–57]. Vinorelbine also disrupts metabolism of amino acid, cyclic AMP, glutathione, nucleic acids and lipid biosynthesis [58]. The sensitivity of cancer cells to vinorelbine has been associated with the expression of MDR1, Pgp, MRP-1, RLIP76, RAF1 genes, and the activation of AKT/ERK proteins [55,59]. It is used as a single treatment or in combination with cisplatin for NSCLC at stage III and as a monotherapy for previously treated patients [60,30]. 2.6.3. Gemcitabine 20 -deoxy-20 ,20 -difluorocytidine monohydrochloride (b-isomer; Gemcitabine) was approved by FDA in 1996. Pharmacology: Gemcitabine inhibits processes required for DNA synthesis. The incorporation of gemcitabine triphosphate (dFdCTP) into DNA replication is the major mechanism by which gemcitabine causes cell death. After incorporation of gemcitabine nucleotide on the end of the elongating DNA strand, one more deoxynucleotide is added, and therefore, DNA polymerases are unable to proceed. It stops normal development and cell division by ribonucleotide reductase inhibition [61]. Lung cancer cells become resistant to gemcitabine due to decreased dCDA activity [62], the activation of NF-kB via and the subsequent overexpression of Bfl-1 [63]. Bfl-1 is a transcriptional target of NF-kB. It interacts and isolates proapoptotic molecules, suppressing apoptosis and inhibiting cytochrome c release from mitochondria [64,65]. Gemcitabine is indicated in combination with cisplatin for the first-line treatment of patients with stage IIIA, IIIB or IV [30,66].
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2.7. Unspecific treatments used as second-line treatments for both, adenocarcinoma and squamous cell carcinoma 2.7.1. Ramucirumab Recombinant human IgG1 monoclonal antibody (Ramucirumab) was approved by the FDA in 2014. Ramucirumab binds to VEGFR-2 and blocks the binding of the VEGF ligand to VEGFR-2, controlling the proliferation and migration of cells [67]. Resistance for ramucirumab has not been reported. Ramucirumab is used with docetaxel for NSCLC with disease progression on or after platinum-based chemotherapy. It is used as a second-line treatment alone or in combination with docetaxel in patients at stage IV of NSCLC after platinum-based therapy [68]. 2.7.2. Docetaxel (2R,3S)-N-carboxy-3-phenylisoserine, N-tert-butyl ester, 13ester with 5b-20-epoxy-1,2a,4,7b,10b,13a-hexahydroxytax-11en-9-one 4-acetate 2-benzoate, trihydrate (Docetaxel) was approved by the FDA in 1999. Pharmacology: It is an antineoplastic agent that belongs to taxane family and inhibits microtubule depolymerization leading the metaphase to anaphase transition arrest and subsequently causing apoptosis [69]. Acquired resistance is related to alterations in the docetaxel metabolism, drug transporters, and deregulation of the cell cycle and apoptosis pathways [70]. However, mutations that abrogate drug binding have been also reported and alterations in microtubule- gene expression and signaling [71]. Docetaxel is used as second line therapy for stage IIIA, IIIB or IV after platinum therapy failure and it can be used in combination with cisplatin [30]. 2.7.3. Erlotinib N-(3-ethynylphenyl)-6,7 bis(2-methoxyethoxy)-4-quinazolinamine (Erlotinib) and was approved by the FDA in 2004. Pharmacology: Erlotinib is small TKI molecule that target EGFR. It binds to the intracellular TK domain of EGFR and blocks its ATPbinding site [72]. Erlotinib acquired resistance is linked to the secondary mutation T790 M [53], MET activation and the methylation of death-associated protein kinase (DAPK). MET is a proto-oncogene that encodes the receptor for the hepatocyte growth factor (HGF) and is associated with promoting cell invasion and metastasis [73]. DAPK is a hypermethylated protein kinase that causes erlotinib resistance [74]. Erlotinib drug is used in stage III or IV as a first-line treatment for NSCLC in patients where EGFR exon 19 deletions or exon 21 substitution mutations are present. Thus, it is used as second- and third-line treatment in patients with EGFR wild-type NSCLC after failed chemotherapy [75,30,76] and in combination with gemcitabine. On October 2016, FDA restricted the use of erlotinib for patients with specific EGFR mutations. 2.7.4. Osimertinib N-(2-{2dimethylaminoethyl-methylamino}-4-methoxy-5-{[4(1-methylindol-3-yl)pyrimidin-2yl]amino}phenyl)prop-2-enamide mesylate salt. (Osimertinib) was approved by the FDA in 2015. Pharmacology: Osimertinib is a kinase inhibitor of EGFR, which binds to EGFR with the following mutations: T790 M, L858R, and exon 19 deletion, over the wild-type form of EGFR [77]. It is a thirdgeneration drug that can deregulate DNA synthesis and proliferation [78]. It is used in patients with EGFR T790 M whose disease has progressed after a first-line TKI treatment [78,79]. 3. Early detection through biomarkers Despite of the evolution of drugs approved for NSCLC treatment, it seems that cisplatin has been one of the most successful molecules discovered that is now combined with some other more specific treatments. However, in the last decade the
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cancer research has moved into the search for early diagnosis using biomarkers, partially, because none of the treatments, alone or in combination are completely effective. By definition, a good biomarker should be a molecule generated exclusively by cancer cells and/or by the tumor microenvironment in sufficient amount to be properly detected in an early stage of the tumor development [80]. Biomarkers can be useful not only for diagnosis but also for prognostic and as a predictive tool for treatment response. The nature of the biomarkers is wide and includes proteins derived from tumors or proteins derived from immune system, but also some other molecules as DNA and miRNAs and polymorphisms and alterations in the gene copy number. Below, a brief description of some of the most promising biomarkers that are being or could be used for early diagnosis. 3.1. Protein biomarkers Classical protein-based circulating biomarkers for various solid tumors have been studied in the last decades including carcinoembryonic antigen (CEA), CYFRA21-1, plasma kallikrein B1 (KLKB1) and neuron-specific enolase [30]. However, specificity is the main inconvenient for lung cancer diagnosis [81]. For instance, CEA was suggested around 2004 to be a biomarker for detection of advanced NSCLC. Patients with levels above 50 ng/mL are considered as positive for this type of cancer and unfortunately is also a poor prognosis biomarker [82]. Lately, was also suggested as biomarker for gastric cancer detection in combination with cancer antigen 19-9 and cancer antigen 72-4 [83]. Until now, there is no specific protein biomarker which could establish the stage of the lung cancer and moreover, more than one biomarker is needed for a more precise diagnosis. The simultaneous detection of at least two proteins is also promising and detection of CEA and CYFRA211 in human serum using quantum dot-doped polystyrene nanoparticles could be used for lung cancer patients [84]. The serum peptidome has been identified using a ZipTip technology with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, identifying C3 and fibrinogen a chain as peptides, specifically derived from NSCLC patients [85]. Thus, new potential biomarkers including KDM1A, a histone demethylase for H3K4me2/me1 demethylation has been proposed as a therapeutic agent against NSCLC, specifically, related to metastasis prediction [86]. 3.2. Biomarkers derived from immune system Immunotherapy is the involvement of immune-mediated therapies designated to destroy tumor cells and in the last decade, specific characteristics of immune cells nested in tumors have been suggested not only as biomarkers but also as therapy. 3.2.1. Tumor infiltrating lymphocytes The microenvironment of a tumor is mainly composed by endothelial cells, fibroblast, and immune cells and particularly, lymphocytes can be detected in different quantities among different types of tumors but also among patients with the same type of cancer. Tumor-infiltrating lymphocytes (TILs) is a complex mixture of immune cells which besides lymphocytes T and B includes also macrophages, natural killer cells and dendritic cells. Specifically, TILs could predict the prognosis in different tumors based on specific antitumor activity of CD4(+) and CD8(+) T cells. For instance, triple-negative breast cancer patients with high population of TILs had better survival than patients with lower TILs cells [87]. More recently, some specific adhesion molecules such as CD103, which kill tumor cells through immune checkpoint receptor PD-1, have been found in TILs of NSCLC patients and have been associated with favorable clinical outcome [88].
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However, there are some issues regarding to the methodology for quantification that are being addressing. For instance, the International TILs Working Group (formed by 32 experts in TILs research) has established that TILs should be analyzed in the stroma within the borders of the invasive tumor excluding TILs outside of the tumor border and dendritic cells and macrophages [89]. In addition, immunohistochemistry with gene expression analysis seems to offer more accuracy for detection than flow cytometry [90]. For NSCLC, TILs subtyped as CD3(+),CD4(+) and CD8(+) have shown the most robustness for prognostics in patients according with a meta-analysis derived from 7006 patients belonging to 24 different studies performed between 2003 and 2015 [91]. In addition, the antitumor effects of TILs have suggested their potential usage as therapeutic strategy. Currently, TILs have been isolating from patients and then, same patient receives the infusion with isolated TILs for melanoma treatment. This research is approved by the National Cancer Institute in USA (Trial IDs: 2643.00, NCI-2013-00486, NCT01807182, Trial IDs: 13-C-0093, NCI-2013-01586, 130093, P131209, NCT01814046) and it is also used against NSCLC that is metastatic or cannot be removed by surgery (Trial IDs: 14-C-0104, NCI-2014-02481, P131510, NCT02133196). 3.2.2. C4d complement split product Immune activation may generate host-derived markers that are more homogeneous than cancer-derived markers. Immune responses against intracellular and surface tumor antigens have been described in lung cancer patients. Lung tumors activate the classical complement pathway and generate C4d, which is a degradation product of this pathway and can be used for diagnosis and prognosis of lung cancer [92]. 3.2.3. Autoantibodies Cancer patients produce autoantibodies to tumor proteins that are expressed abnormally. The autoantibody test detects early stages of lung cancer and has worked effectively on a large number of individuals from a routine clinical practice setting [93]. 3.3. Circulating tumor cells (CTCs) As a result of constant tumor-cell growth and death, solid tumors release substantial amounts of material into the bloodstream, including circulating tumor cells (CTCs) [30]. CTCs can be sampled in peripheral blood, and they are considered a noninvasive alternative to tissue biopsies for diagnosis of lung cancers [94] using cytokeratins (CK), TTF-1, CD56 and VEGFR2 as CTCs markers, normally detected as different sub-populations [95]. CTCs could be more sensitive for early diagnosis of lung cancer than blood serum markers such as cyfra21-1 or CEA [96]. EGFR mutations, ALK-rearranged pattern, and ROS1 rearrangement have been identified in CTCs from metastatic NSCLC [30]. Understanding metastasis-initiating capabilities of CTCs from primary lung cancer will provide specific adjuvant therapies targeting CTCs to reduce metastasis and improve survival [96]. The quantitation of these cells can yield prognostic information that could be related to tumor biology or burden. One counting method is the CellSearch1 (https://www.cellsearchctc.com/), and is FDA-approved for monitoring patients with advanced-stage cancer. CTCs can be characterized at molecular level, to identify the origin and to obtain biological information about the tumor. Detection of 50CTCs/ 7.5 ml of blood before chemotherapy was associated with an unfavorable clinical outcome compared to patients with
