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Fibroblast growth factor receptor 2: a therapeutic target in gastric cancer Expert Rev. Gastroenterol. Hepatol. 7(8), 759–765 (2013)
Liu Hong*1‡, Yu Han2‡, Jinqiang Liu1‡ and Lubi Brain3 1 State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, Shaanxi Province, China 2 Department of Otolaryngology, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, Shaanxi Province, China 3 The Sidney Kimmel Comprehensive Cancer Center, Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA *Author for correspondence: Tel.: +86 298 477 3974 Fax: +86 298 253 9041 [email protected] ‡
Authors contributed equally
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Gastric cancer remains a leading cause of cancer-related death in the world. FGF receptor 2 (FGFR2) is preferentially amplified and overexpressed in the diffuse type of gastric cancer. This review evaluates the expression and function of FGFR2 in gastric cancer, and analyzes the use of its inhibitors for gastric cancer therapy. This review also discusses the limitations of FGFR2-based therapy, and envisages future developments toward the clinical applications of FGFR2. KEYWORDS: apoptosis • drug resistance • fibroblast growth factor • fibroblast growth factor receptor 2 • gastric cancer • growth • prognosis • target • therapy
Gastric cancer is one of the most common cancers in the world. Despite considerable improvements in clinical diagnostics and surgical techniques, advanced gastric cancer remains a leading cause of cancer-related death worldwide, second only to lung cancer [1]. Effective treatment of gastric cancer is urgently needed. Gastric cancer is a genetic disease that involves multiple epigenetic changes and genetic alterations of cancer-associated molecules. The understanding of gastric cancer biology results in the development of molecular targeted agents with the potential to suppress key pathways involved in gastric carcinogenesis. Many molecular agents, such as VEGF, HER2, have been used either as single-targeted approach or in combination with traditional chemotherapeutic drugs in treatment of gastric cancer [2]. There are two distinct pathological types of gastric cancer: the intestinal type and the diffuse type [3]. Diffuse-type gastric cancer is considered to be de novo cancer, and it harbors aberrations in the FGF receptor (FGFR) 2/ ErbB3/PI3 kinase pathways. FGFR2 gene, originally isolated from gastric cancer cell line KATO-III, is preferentially amplified and overexpressed in diffuse-type gastric cancer [4]. FGFR2 plays important roles in the development and progression of diffuse-type gastric cancer through regulation of many pathways, such as PI3K-AKT, RAS-ERK and DAG-PKC cascades [5].
10.1586/17474124.2013.837804
To date, the personalized medicine prescribing targeted drugs has being developed quickly. This review summaries the role of FGFR2 in gastric cancer and further envisage the promising application of FGFR2 in gastric cancer targeted therapy. Fibroblast growth factor signals & fibroblast growth factor receptor family
FGFs are involved in fetal morphogenesis, adult tissue homeostasis and tumorigenesis [6]. FGFs play important roles in a variety of cellular processes, such as cell proliferation, stemness, apoptosis, angiogenesis and drug resistance [7]. The secreted-type ligands of the FGF family, including FGF1–10 and FGF16– 23, bind to multiple FGFRs to transduce signals in target cells. FGF triggers the autophosphorylation of FGFR, which results in a structural change of the tyrosine kinase domain, thus phosphorylating other tyrosine residues at substrate-binding sites along with FGFR-bound adaptor molecules. FGF signals will induce the activation of RAS-ERK, PI3KAKT, DAG-PKC/PKD signaling cascade and IP3-mediated Ca2+ release [8]. FGF signaling cascades interact with Notch, WNT, Hedgehog and BMP signaling cascades to maintain the homeostasis among stem and progenitor cells [9]. The FGFR family comprises four tyrosine kinase receptors: FGFR1, 2, 3, 4 [10]. They
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share a common domain architecture consisting of extracellular immunoglobulin-like domains and cytoplasmic tyrosine kinase domain. FGFR genes are proto-oncogenes activated in human cancers as a result of gene amplification, chromosomal translocation and point mutation [4]. FGFR2 gene, located at human chromosome 10q26, is characterized by its amplification and overexpression in the diffuse-type gastric cancer [11]. FGFR2 is regulated on the basis of the balance of FGFs, heparan-sulfate proteoglycans, FGFR2 isoforms and endogenous inhibitors [12]. FGFR2b and FGFR2c are FGFR2 isoforms [13]. FGFR2b isoform, consisting of exons 1–6, 8, 9, 11–19 and 21, is predominantly expressed in epithelial cells. FGFR2c isoform, consisting of exons 1–6, 8, 10–19 and 21, is preferentially in mesenchymal cells. FGFR2b functions as the receptor for FGF1, FGF3, FGF7, FGF10 and FGF22, while FGFR2c for FGF1, FGF2, FGF4, FGF6, FGF9, FGF16 and FGF20. Activation of FGFR2b and FGFR2c will result in ligand-independent FGF signaling, thus playing important roles in the development of diffuse-type gastric cancer (FIGURE 1). Expression of FGFR2 in gastric cancer
Yamashita et al. have found that diffuse-type gastric cancer harbors aberrations in the FGFR2/ErbB3/PI3 kinase pathway, while intestinal-type gastric cancer has an activated ErbB2 oncogenic pathway [14]. Guo et al. have found that almost all intestinal-type gastric cancer tumors overexpressed at least one of a panel of three proteins, MET, FGFR2 and EPHA2 [15]. Matsumoto et al. have found that FGFR2 amplification was observed in 4.1% (11 out of 267) of gastric cancers [16]. No amplification of the three other FGFR family members (FGFR1, 3 and 4) was detected. A FISH analysis was performed on 7 cases among 11 FGFR2-amplified cases and showed that 6 of these 7 cases were highly amplified, while the remaining 1 had a relatively low grade of amplification. Although the difference was not significant, patients with FGFR2 amplification tended to exhibit a shorter overall survival period. Kim et al. have found that the combined Diffuse-type gastric cancer
FGF
FGFR2 amplification
FGF signals
RAS-ERK
PI3K-AKT
DAG-PKC/PKD
IP3–Ca2+ release
Regulation of cell growth, apoptosis, drug resistance
Figure 1. FGF signalling in diffuse-type gastric cancer. FGFR2: FGF receptor 2.
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expression of MYC, EGFR and FGFR2 was predictive of poor survival in cisplatin and 5-fluorouracil (5-FU)-treated metastatic gastric cancer patients [17]. The FGFR2 gene is homologous to other genes, including K-sam and KGFR [18]. Overexpression of FGFR2/K-sam is correlated with poor prognosis in gastric cancer. Hattori et al. have examined the expression of the FGFR2/K-sam protein in 38 cases of gastric cancer by immunohistochemistry [18]. Totally 20 cases (52.63%) of the undifferentiated type of advanced gastric cancer were K-sam positive. The K-sam protein was detected only focally in the primary tumor, with strong staining in the metastasized tumor in the lymph node and liver. Toyokawa et al. have found that the prognosis of K-sampositive gastric cancer patients was significantly poorer than that of K-sam-negative patients [19]. Genetic variations, especially single nucleotide polymorphisms (SNPs), are involved in the functional activation of FGFR2 protein during carcinogenesis. SNPs of the FGFR2 gene are associated with an increased risk of estrogen receptor-positive breast cancer [20]. The association between SNPs of the FGFR2 gene and diffuse-type gastric cancer remains unknown. Katoh has reported that gain-of-function mutations or variations of FGFR2 occurred in estrogen receptor-positive breast cancer, diffuse-type gastric cancer and endometrial uterine cancer [21]. Jang et al. have reported two identical mutations in FGFR2 that caused craniosynostosis syndromes, Crouzon, Apert and Pfeiffer syndromes in gastric carcinoma [22]. A missense mutation (Ser267Pro) in exon IIIa and a splice site mutation (940-2A–>G) in exon IIIc were detected in gastric cancer patients. Functions & mechanism of FGFR2 in gastric cancer
Inhibitors of FGFR2 may have therapeutic efficacy in the subset of gastric cancers containing FGFR2 amplification (TABLE 1). Kunii et al. have found that FGFR2-amplified gastric cancer cell lines required FGFR2 and Erbb3 signaling for growth and survival [23]. FGFR2 was overexpressed and tyrosine phosphorylated selectively in FGFR2-amplified gastric cancer cell lines KATOIII, SNU-16 and OCUM-2M. Inhibition of FGFR2 kinase by a specific small-molecule inhibitor, PD173074, resulted in growth inhibition and cell cycle arrest in KATO-III cells, and induced apoptosis in both SNU-16 and OCUM-2M cells. In FGFR2-amplified gastric cancer cell lines, the elevated expression of EGFR, Her2 and Erbb3 phosphotyrosine was dependent on FGFR2, revealing that EGFR family kinases were downstream targets of amplified FGFR2. Matsumoto et al. have found that FGFR2 amplification could confer hypersensitivity to FGFR inhibitor in gastric cancer cell lines [16]. Park et al. have found that the epigenetic silencing of FGFR2 through DNA methylation might play important roles in gastric carcinogenesis [24]. The restoration of FGFR2 expression by treating methylated gastric cancer cells with the DNA methyltransferase inhibitor 5-aza2´-deoxycytidine strongly suggested that the loss of FGFR2 expression might be due to the aberrant hypermethylation in the promoter region of the FGFR2 gene. Expert Rev. Gastroenterol. Hepatol. 7(8), (2013)
FGFR2 & gastric cancer
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Table 1. The role of anti-FGF receptor 2 agents in gastric cancer. Agent
Type
Method
Effect
PD173074
Preclinical
In vitro
Induce growth inhibition and apoptosis of gastric cancer cells
[23]
AZD2171
Preclinical
In vitro/vivo
Induce growth inhibition of gastric cancer cells
[25]
AZD4547
Preclinical
In vitro/vivo
Induce growth inhibition and apoptosis of gastric cancer cells
[26]
S49076
Preclinical
In vitro/vivo
Inhibit growth and reverse drug resistance of gastric cancer cells
[27]
GP369
Preclinical
In vitro/vivo
Induce growth inhibition of gastric cancer cells
[28]
Ki23057
Preclinical
In vitro/vivo
Inhibit growth and reverse drug resistance of gastric cancer cells
[30]
Brivanib
Phase I trial
Clinical trial
Brivanib plus cetuximab lead to 9.7% response of gastrointestinal patients
[33]
AZD2171 completely inhibits the phosphorylation of FGFR2 and downstream signaling proteins, such as FRS2, AKT and mitogen-activated protein kinase [25]. AZD2171 also inhibits other receptor tyrosine kinases, such as PDGFRA, PDGFRB, KIT, VEGFR1, VEFGR2 and VEGFR3. AZD2171 can directly inhibit the growth of two gastric cancer cell lines KATO-III and OCUM-2M, which overexpress FGFR2 [25]. Oral administration of AZD2171 can significantly and dosedependently inhibit in vivo proliferation of cancer cells with aberrant FGFR2 activation in rodent therapeutic models. AZD4547 effectively inhibits the phosphorylation of FGFR2 [26]. Xie et al. have found that FGFR2 gene amplification in gastric cancer could predict sensitivity to AZD4547 [26]. The gastric cancer cell lines carrying the amplified FGFR2 gene, SNU-16 and KATO-III, were extremely sensitive to AZD4547 in vitro. AZD4547 could effectively induce apoptosis of SNU-16 cells by inhibiting the downstream signaling molecules of FGFR2. Furthermore, inhibition of FGFR2 signaling by AZD4547 resulted in significant dose-dependent tumor growth inhibition in FGFR2-amplified xenograft and patient-derived gastric cancer xenograft models, but not in non-amplified models. shRNA knockdown of FGFR2 led to similar inhibition of tumor growth in vitro and in vivo. Comparing with monotherapy, AZD4547 in combination with chemotherapeutic agents showed enhancement of in vivo anti-tumor efficacy. Taken together, FGFR2 pathway activation was required for driving growth and survival of gastric cancer carrying FGFR2 gene amplification both in vitro and in vivo. Burbridge et al. have described the preclinical characterization of S49076, a novel inhibitor of FGFR2 [27]. S49076 could also potently block cellular phosphorylation of MET, AXL/MER, FGFR1, FGFR3 and inhibited downstream signaling in vitro and in vivo. In cell models, S49076 inhibited the proliferation of FGFR2-dependent gastric cancer cells, and inhibited colony formation of hepatocarcinoma cells expressing FGFR1/2 and AXL. In tumor xenograft models, oral administration of S49076 could significantly inhibit tumor growth. FGFRs have been implicated in resistance to VEGF/VEGFR inhibitors, such as bevacizumab. S49076 alone could induce tumor growth arrest in bevacizumab-resistant tumors. Moreover, combination www.expert-reviews.com
Ref.
of S49076 with bevacizumab in cancer xenograft models led to near total inhibition of tumor growth. Dysregulated FGFR2 signaling is one of the critical oncogenic pathways involved in the initiation and/or maintenance of tumors. Bai et al. have found that GP369, an FGFR2-IIIb-specific antibody, could exhibit potent antitumor activity against gastric cancers driven by activated FGFR2 signaling [28]. They discovered that gastric cancer cell lines harboring FGFR2 amplification predominantly expressed the IIIb isoform of the receptor. GP369 could specifically and potently suppress ligand-induced phosphorylation of FGFR2-IIIb and downstream signaling, as well as FGFR2-driven proliferation in vitro. The administration of GP369 in mice could significantly inhibit the growth of human cancer xenografts harboring activated FGFR2 signaling. Thus, cancer patients with aberrantly activated/amplified FGFR2 signaling could potentially benefit from therapeutic intervention with FGFR2-targeting antibodies. Scirrhous gastric carcinoma carries the highest mortality because of a frequent metastasis to lymph node. A FGFR2 phosphorylation inhibitor or TGFbetaR inhibitor appears therapeutically promising in scirrhous gastric carcinoma [29]. Yashiro et al. have found that a FGFR2 phosphorylation inhibitor could prolong the survival of mice with peritoneal metastasis of scirrhous gastric cancer. Nakamura et al. have found that the FGFR2 phosphorylation inhibitor, Ki23057, appeared therapeutically promising in scirrhous gastric carcinoma [30]. Ki23057 could significantly inhibit the proliferation of scirrhous cancer cells but not non-scirrhous gastric carcinoma cells. The oral administration of Ki23057 could significantly prolong survival of mice with injection of OCUM-2MD3 scirrhous cancer cells. Kataoka et al. have found that foretinib, an oral multikinase inhibitor known to target MET, RON, AXL and vascular endothelial growth factor receptors, could effectively inhibit the growth of gastric cancer cells harboring not only MET but also FGFR2 amplification by blocking inter-RTK signaling networks [31]. Pan et al. have found that MK-2461, a novel ATP-competitive multitargeted inhibitor of activated c-Met, displayed significant inhibitory activities against FGFR [32]. 761
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Brivanib is an oral dual inhibitor of FGFR and VEGFR signaling pathways. Garrett et al. have performed a Phase I study to determine the safety and efficacy of brivanib combined with cetuximab in patients with advanced gastrointestinal malignancies [33]. The most common treatment-related toxicities were fatigue, diarrhea and anorexia. A total of 62 patients received brivanib (320, 600 or 800 mg daily) plus cetuximab (400 mg/ m2 loading dose then 250 mg/m2 weekly), and 6 (9.7%) patients had objective radiographic partial responses. The median duration of response and median progression-free survival was 9.2 and 3.9 months, respectively. Park et al. have carried out a Phase II study of brivanib as first-line therapy in patients with advanced hepatocellular carcinoma [34]. Brivanib demonstrated promising antitumor activity and a manageable safety profile in 55 cases of patients. Brivanib was generally well tolerated, and the 6-month progression-free survival rate was 18.2%. Ponatinib (AP24534) is an oral multitargeted kinase inhibitor that potently inhibits the in vitro kinase activity of all four members of the FGFR family [35]. In a panel of 14 cell lines representing various tumor types, including gastric cancer, ponatinib can inhibit FGFR-mediated signaling and inhibited cell growth. Daily oral dosing of ponatinib (10–30 mg/kg) to mice reduced tumor growth and inhibited signaling in all three tumor models examined. Gozgit et al. have found that combined targeting of FGFR2 and mTOR by ponatinib and ridaforolimus results in synergistic antitumor activity in FGFR2 mutant endometrial cancer models [36]. LY2874455 is also a potent inhibitor of all four members of the FGFR family [37]. LY2874455 exhibits a potent activity against FGF/ FGFR-mediated signaling in gastric cancer cell lines, and shows anti-tumor activity in gastric cancer xenograft models. Effect of FGFR2 on drug resistance of gastric cancer cells
Drug resistance is a big obstacle for gastric cancer therapy [38]. FGFR inhibitors can enhance the sensitivity to conventional anticancer drugs, such as 5-FU, irinotecan, paclitaxel and etoposide, in human cancer cells with aberrant FGFR activation [39]. Because there are multiple mechanisms of action for FGFR inhibitors to overcome drug resistance in human cancer, FGFR-targeted therapy is a promising strategy for the treatment of drug-resistant gastric cancer. Ki23057 is a broad-range tyrosine kinase inhibitor, inhibiting FGFR1, FGFR2 and VEGF2 tyrosine kinases. Qiu et al. have found that Ki23057 could enhance the chemosensitivity of drug-resistant gastric cancer cells, especially when used in combination with irinotecan, paclitaxel or etoposide [40]. The effects of the combination of Ki23057 with anticancer drugs on proliferation and apoptosis were examined in five gastric cancer cells with resistance to irinotecan, paclitaxel, etoposide, oxaliplatin and gemcitabine, respectively. Ki23057 could significantly enhance the apoptosis rates induced by chemotherapeutic drugs in both the drug-resistant cell lines and the parental cell line. Ki23057 could significantly decrease the IC50 values 762
of cancer cells resistant to irinotecan, paclitaxel or etoposide, but not the cells resistant to oxaliplatin, and gemcitabine. Ki23057 could decrease the ERCC1 expression level and increase the p53 expression level in the cancer cells resistant to irinotecan, paclitaxel or etoposide, indicating that ERCC1 and p53 may play an integral role in the synergism between Ki23057 and chemotherapeutic agents. Yashiro et al. have found the combined treatment with 5-FU and Ki23057 produced synergistic anti-tumor effects for scirrhous gastric cancer treatment [41]. Ki23057 at 100 nM could significantly inhibit the proliferation and decrease the phosphorylation of FGFR2 in scirrhous gastric cancer cells, but not in nonscirrhous gastric cancer cells. The combination of Ki23057 and 5-FU showed synergistic antitumor effects for scirrhous gastric cancer cells by decreasing DPD expression and increasing p21 expression. The combined administration of Ki23057and S1 could significantly decrease the growth of orthotopic tumors and lymph node metastasis more effectively than S1 alone. Expert commentary
Gastric cancer is one of most common malignancies in the world. Despite a reduction in mortality, gastric cancer still represents a leading cause of death worldwide. Recently, more and more studies have investigated the therapeutic value of molecularly targeted agents in gastric cancer [42]. Since FGF signaling is involved in various aspects of cancer biology, FGFR-targeted therapy is an active topic in the field of clinical oncology. FGFR2 overexpression or mutation is significantly related with diffuse types of gastric cancer. Inhibitors of FGFR2 can significantly inhibit the proliferation of gastric cancer cells with FGFR2 mutation or gene amplification. FGFR inhibitors can also overcome the drug resistance of gastric cancer cells. Furthermore, inhibitors of FGFR2 show synergistic anti-tumor effects for gastric cancer cells in combination with chemotherapeutic drugs. Thus, FGFR2 is considered as an important target for gastric cancer treatment. The use of FGFR2 inhibitors for therapy of gastric cancer patients with FGFR2 mutation or gene amplification is a promising strategy. Since the inhibitors of FGFR2 have demonstrated encouraging efficacy in early phase trials, future treatment options for gastric cancer appear bright. However, many questions remain to be answered: What is the relation between FGFR2 SNPs and risk of diffuse-type gastric cancer? What is the mechanism of FGFR2 in drug resistance of gastric cancer? How to select the right set of patients that can benefit from anti-FGFR2 therapy? What is the side effect of anti-FGFR2 therapy? More in vivo assay and clinical trials are needed to evaluate the effect of combined therapy of anti-FGFR2 inhibitors and traditional therapeutic drugs. Five-year view
Although the FGFR2-based therapy seems to have a potential role in gastric cancer patients, the results of more clinical trials are still pending. More investigations should be performed along the following avenues that are likely to lead to exciting results. Expert Rev. Gastroenterol. Hepatol. 7(8), (2013)
FGFR2 & gastric cancer
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Identification of the mechanisms of FGFR2 in gastric cancer
There is diversity of molecular changes acquired during gastric carcinogenesis [43]. FGFR2-related FGF signaling cascades play an important role in gastric carcinogenesis through regulation of cancer stem cells, cell proliferation, apoptosis and angiogenesis. In different gastric cancer cells, FGFR2 can regulate diverse pathways. Continued basic studies are warranted to gain more insights into the molecular mechanisms of FGFR2 in cancer development and progression. Understanding the regulatory network of FGFR2 in drug resistance of gastric cancer will lead to possible improvements in personalized therapeutics. Characterization of FGFR2-induced critical alterations will help to find novel therapeutic targets for gastric cancer. Identification of the biomarkers of FGFR2-based therapy
The inhibitors of FGFR are promising anticancer drugs for certain diffuse-type gastric cancer patients carrying FGFR2 gene amplification. A great challenge is the identification of biomarkers that can help to select the right patient candidate to FGFR2-based therapy. FISH analyses, utilized for the detection of gene amplification of FGFR2, can be used to facilitate patient selection. Immunohistochemistry can also be used to detect the expression of FGFR2 in normal gastric tissues [44] and gastric cancer tissues [45]. Analysis of SNPs or copy number polymorphism (CNP) in FGF signaling genes will give information on the sensitivity to FGFR2-based therapy. Whole exome/ transcriptome sequencing will play a crucial role to identify the right patient population in the era of personalized medicine. Identification of the side effects of FGFR2-based therapy
Since dysregulation of FGFR2 signaling is involved in both cancer and congenital disorders [46], the safety of FGFR2-based
Review
therapy should be carefully evaluated before future clinical application. Tyrosine kinase inhibitors, human antibody, peptide mimetic and siRNA are potential technologies to be applied for anti-FGFR2 therapy. The long-term safety of these anti-FGFR2 inhibitors need to be investigated in animal models. An ideal anti-FGFR2 inhibitor will lead to the effective therapeutic outcomes without any unanticipated side effects. It is also necessary to investigate the toxicity resulting from the addition of anti-FGFR2 agents to traditional cytotoxic chemotherapy. Identification of the strategy of combination therapy
Monotherapy with anti-FGFR2 inhibitors may be less toxic, but less efficient either. Anti-FGFR2 inhibitors can decrease the drug resistance of cancer cells, thus improving the efficacy of current chemotherapeutic drugs. In order to improve the efficacy of single-agent therapy, further studies will be required to establish the most effective combinations of anti-FGFR2 inhibitors and other drugs with minimal side effect. The combination of FGFR2 targeted agents with chemotherapeutic drugs based on a patient’s molecular profile may deliver better responses. Financial & competing interests disclosure
This study was supported in part by grants from the National Natural Scientific Foundation of China (81100714, 81171923), the Foundation of Shaanxi Province Science and Technology research (2012KJXX-20) and the Top PhD Foundation of China (201075). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues • Gastric cancer remains a leading cause of death worldwide, and effective target therapy is urgently needed. • FGF receptor 2 (FGFR2) is preferentially amplified and overexpressed in the diffuse-type gastric cancer. • Inhibitors of FGFR2 can induce growth inhibition, apoptosis and drug sensitivity of gastric cancer cells in vitro and in vivo. • Inhibitors of FGFR2 show synergistic anti-tumor effects for gastric cancer cells in combination with chemotherapeutic drugs. • FGFR2 is considered as one valuable target for gastric cancer treatment. • More clinical trials should be performed to promote the use of FGFR2 in clinic.
References
3
Yasui W, Sentani K, Sakamoto N, Anami K, Naito Y, Oue N. Molecular pathology of gastric cancer: research and practice. Pathol. Res. Pract. 207(10), 608–612 (2011).
6
Kumar SB, Narasu L, Gundla R, Dayam R, J A R P S. Fibroblast growth factor receptor inhibitors. Curr. Pharm. Des. 19(4), 687–701 (2013).
4
Katoh Y, Katoh M. FGFR2-related pathogenesis and FGFR2-targeted therapeutics. Int. J. Mol. Med. 23(3), 307–311 (2009).
7
5
Katoh M, Katoh M. FGF signaling network in the gastrointestinal tract. Int. J. Oncol. 29(1), 163–168 (2006).
Brooks AN, Kilgour E, Smith PD. Molecular pathways: fibroblast growth factor signaling: a new therapeutic opportunity in cancer. Clin. Cancer Res. 18(7), 1855–1862 (2012).
8
Katoh M, Nakagama H. FGF receptors: cancer biology and therapeutics. Med. Res.
Papers of special note have been highlighted as: • of interest •• of considerable interest 1
Smyth EC, Cunningham D. Targeted therapy for gastric cancer. Curr. Treat. Options. Oncol. 13(3), 377–389 (2012).
2
De Vita F, Giuliani F, Silvestris N et al. Current status of targeted therapies in advanced gastric cancer. Expert. Opin. Ther. Targets 16(Suppl. 16), S29–S34 (2012).
www.expert-reviews.com
763
Review
Hong, Han, Liu & Brain
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by V U L Periodicals Rec on 12/28/14 For personal use only.
Rev. doi:10.1002/med.21288 (2013) (Epub ahead of print). ••
An overview of FGF receptors (FGFRs) in cancer therapy.
9
Katoh M. Cancer genomics and genetics of FGFR2 (Review). Int. J. Oncol. 33(2), 233–237 (2008).
10
Katoh M. FGFR2 abnormalities underlie a spectrum of bone, skin, and cancer pathologies. J. Invest. Dermatol. 129(8), 1861–1867 (2009).
11
12
13
14
15
16
Katoh M, Katoh M. Recombination cluster around FGFR2-WDR11-HTPAPL locus on human chromosome 10q26. Int. J. Mol. Med. 11(5), 579–583 (2003). Xu R, Rudd TR, Hughes AJ, Siligardi G, Fernig DG, Yates EA. Analysis of the fibroblast growth factor receptor (FGFR) signalling network with heparin as coreceptor: evidence for the expansion of the core FGFR signalling network. FEBS J. 280(10), 2260–2270 (2013). Christensen C, Berezin V, Bock E. Neural cell adhesion molecule differentially interacts with isoforms of the fibroblast growth factor receptor. Neuroreport 22(15), 727–732 (2011). Yamashita K, Sakuramoto S, Watanabe M. Genomic and epigenetic profiles of gastric cancer: potential diagnostic and therapeutic applications. Surg. Today 41(1), 24–38 (2011). Guo T, Fan L, Ng WH et al. Multidimensional Identification of Tissue Biomarkers of Gastric Cancer. J Proteome Res. (2012) (Epub ahead of print).
Rev. Anticancer Ther. 10(9), 1375–1379 (2010). 21
22
Garrett CR, Siu LL, El-Khoueiry A et al. Phase I dose-escalation study to determine the safety, pharmacokinetics and pharmacodynamics of brivanib alaninate in combination with full-dose cetuximab in patients with advanced gastrointestinal malignancies who have failed prior therapy. Br. J. Cancer 105(1), 44–52 (2011).
•
Park S, Kim JH, Jang JH. Aberrant hypermethylation of the FGFR2 gene in human gastric cancer cell lines. Biochem. Biophys. Res. Commun. 357(4), 1011–1015 (2007).
A clinical trial of brivanib plus cetuximab in patients with advanced gastrointestinal malignancies.
34
Takeda M, Arao T, Yokote H et al. AZD2171 shows potent antitumor activity against gastric cancer over-expressing fibroblast growth factor receptor 2/ keratinocyte growth factor receptor. Clin. Cancer Res. 13(10), 3051–3057 (2007).
Park JW, Finn RS, Kim JS et al. Phase II, open-label study of brivanib as first-line therapy in patients with advanced hepatocellular carcinoma. Clin. Cancer Res. 17(7), 1973–83 (2011).
35
Xie L, Su X, Zhang L et al. FGFR2 gene amplification in gastric cancer predicts sensitivity to the selective FGFR inhibitor AZD4547. Clin. Cancer Res. 19(9), 2572–2583 (2013).
Gozgit JM, Wong MJ, Moran L et al. Ponatinib (AP24534), a multitargeted pan-FGFR inhibitor with activity in multiple FGFR-amplified or mutated cancer models. Mol. Cancer Ther. 11(3), 690–699 (2012).
36
Gozgit JM, Squillace RM, Wongchenko MJ et al. Combined targeting of FGFR2 and mTOR by ponatinib and ridaforolimus results in synergistic antitumor activity in FGFR2 mutant endometrial cancer models. Cancer Chemother. Pharmacol. 71(5), 1315–1323 (2013).
37
Zhao G, Li WY, Chen D et al. A novel, selective inhibitor of fibroblast growth factor receptors that shows a potent broad spectrum of antitumor activity in several tumor xenograft models. Mol. Cancer Ther. 10(11), 2200–2210 (2012).
38
Yashiro M, Chung YS, Nishimura S, Inoue T, Sowa M. Peritoneal metastatic model for human scirrhous gastric carcinoma in nude mice. Clin. Exp. Metastasis. 14(1), 43–54 (1996).
Zhang D, Fan D. New insights into the mechanisms of gastric cancer multidrug resistance and future perspectives. Future Oncol. 6(4), 527–537 (2010).
39
Nakamura K, Yashiro M, Matsuoka T et al. A novel molecular targeting compound as K-samII/FGF-R2 phosphorylation inhibitor, Ki23057, for Scirrhous gastric cancer. Gastroenterology 131(5), 1530–1541 (2006).
Chaffer CL, Dopheide B, Savagner P, Thompson EW, Williams ED. Aberrant fibroblast growth factor receptor signaling in bladder and other cancers. Differentiation 75(9), 831–842 (2007).
40
Qiu H, Yashiro M, Zhang X, Miwa A, Hirakawa K. A FGFR2 inhibitor, Ki23057, enhances the chemosensitivity of drug-resistant gastric cancer cells. Cancer Lett. 307(1), 47–52 (2011).
25
26
27
18
Hattori Y, Itoh H, Uchino S, Hosokawa K et al. Immunohistochemical detection of K-sam protein in stomach cancer. Clin. Cancer Res. 2(8), 1373–1381 (1996).
29
Toyokawa T, Yashiro M, Hirakawa K. Co-expression of keratinocyte growth factor and K-sam is an independent prognostic factor in gastric carcinoma. Oncol. Rep. 21(4), 875–880 (2009).
30
764
33
24
Matsumoto K, Arao T, Hamaguchi T et al. FGFR2 gene amplification and clinicopathological features in gastric cancer. Br. J. Cancer. 106(4), 727–732 (2012).
Katoh M. Genetic alterations of FGF receptors: an emerging field in clinical cancer diagnostics and therapeutics. Expert
Pan BS, Chan GK, Chenard M et al. MK2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 70(4), 1524–1533 (2010).
Kunii K, Davis L, Gorenstein J et al. FGFR2-amplified gastric cancer cell lines require FGFR2 and Erbb3 signaling for growth and survival. Cancer Res. 68(7), 2340–2348 (2008).
Kim HK, Choi IJ, Kim CG et al. Three-gene predictor of clinical outcome for gastric cancer patients treated with chemotherapy. Pharmacogenomics J. 12(2), 119–127 (2012).
20
Jang JH, Shin KH, Park JG. Mutations in fibroblast growth factor receptor 2 and fibroblast growth factor receptor 3 genes associated with human gastric and colorectal cancers. Cancer Res. 61(9), 3541–3543 (2001).
32
23
17
19
Katoh M. Dysregulation of stem cell signaling network due to germline mutation, SNP, Helicobacter pylori infection, epigenetic change and genetic alteration in gastric cancer. Cancer Biol. Ther. 6(6), 832–839 (2007).
inhibitor of MET and VEGFRs, inhibits growth of gastric cancer cell lines by blocking inter-receptor tyrosine kinase networks. Invest. New Drugs 30(4), 1352–1360 (2012).
28
31
Burbridge MF, Bossard CJ, Saunier C et al. S49076 is a novel kinase inhibitor of MET, AXL and FGFR with strong preclinical activity alone and in association with bevacizumab. Mol. Cancer Ther. (2013) (Epub ahead of print). Bai A, Meetze K, Vo NY et al. GP369, an FGFR2-IIIb-specific antibody, exhibits potent antitumor activity against human cancers driven by activated FGFR2 signaling. Cancer Res. 70(19), 7630–7639 (2010).
Kataoka Y, Mukohara T, Tomioka H et al. Foretinib (GSK1363089), a multi-kinase
Expert Rev. Gastroenterol. Hepatol. 7(8), (2013)
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by V U L Periodicals Rec on 12/28/14 For personal use only.
FGFR2 & gastric cancer
41
Yashiro M, Shinto O, Nakamura K et al. Synergistic antitumor effects of FGFR2 inhibitor with 5-fluorouracil on scirrhous gastric carcinoma. Int. J. Cancer 126(4), 1004–1016 (2010).
42
Asaoka Y, Ikenoue T, Koike K. New targeted therapies for gastric cancer. Expert Opin. Investig. Drugs 20(5), 595–604 (2011).
•
A review of targeted therapies in gastric cancer.
www.expert-reviews.com
43
Deng N, Goh LK, Wang H et al. A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut 61(5), 673–684 (2012).
44
Hughes SE. Differential expression of the fibroblast growth factor receptor (FGFR) multigene family in normal human adult tissues. J. Histochem. Cytochem. 45(7), 1005–1019 (1997).
Review
45
La Rosa S, Uccella S, Erba S et al. Immunohistochemical detection of fibroblast growth factor receptors in normal endocrine cells and related tumors of the digestive system. Appl. Immunohistochem. Mol. Morphol. 9(4), 319–328 (2001).
46
Katoh M, Katoh M. FGFR2 and WDR11 are neighboring oncogene and tumor suppressor gene on human chromosome 10q26. Int. J. Oncol. 22(5), 1155–1159 (2003).
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Review
Fibroblast growth factor receptor 2: a therapeutic target in gastric cancer Expert Rev. Gastroenterol. Hepatol. 7(8), 759–765 (2013)
Liu Hong*1‡, Yu Han2‡, Jinqiang Liu1‡ and Lubi Brain3 1 State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, Shaanxi Province, China 2 Department of Otolaryngology, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, Shaanxi Province, China 3 The Sidney Kimmel Comprehensive Cancer Center, Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA *Author for correspondence: Tel.: +86 298 477 3974 Fax: +86 298 253 9041 [email protected] ‡
Authors contributed equally
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Gastric cancer remains a leading cause of cancer-related death in the world. FGF receptor 2 (FGFR2) is preferentially amplified and overexpressed in the diffuse type of gastric cancer. This review evaluates the expression and function of FGFR2 in gastric cancer, and analyzes the use of its inhibitors for gastric cancer therapy. This review also discusses the limitations of FGFR2-based therapy, and envisages future developments toward the clinical applications of FGFR2. KEYWORDS: apoptosis • drug resistance • fibroblast growth factor • fibroblast growth factor receptor 2 • gastric cancer • growth • prognosis • target • therapy
Gastric cancer is one of the most common cancers in the world. Despite considerable improvements in clinical diagnostics and surgical techniques, advanced gastric cancer remains a leading cause of cancer-related death worldwide, second only to lung cancer [1]. Effective treatment of gastric cancer is urgently needed. Gastric cancer is a genetic disease that involves multiple epigenetic changes and genetic alterations of cancer-associated molecules. The understanding of gastric cancer biology results in the development of molecular targeted agents with the potential to suppress key pathways involved in gastric carcinogenesis. Many molecular agents, such as VEGF, HER2, have been used either as single-targeted approach or in combination with traditional chemotherapeutic drugs in treatment of gastric cancer [2]. There are two distinct pathological types of gastric cancer: the intestinal type and the diffuse type [3]. Diffuse-type gastric cancer is considered to be de novo cancer, and it harbors aberrations in the FGF receptor (FGFR) 2/ ErbB3/PI3 kinase pathways. FGFR2 gene, originally isolated from gastric cancer cell line KATO-III, is preferentially amplified and overexpressed in diffuse-type gastric cancer [4]. FGFR2 plays important roles in the development and progression of diffuse-type gastric cancer through regulation of many pathways, such as PI3K-AKT, RAS-ERK and DAG-PKC cascades [5].
10.1586/17474124.2013.837804
To date, the personalized medicine prescribing targeted drugs has being developed quickly. This review summaries the role of FGFR2 in gastric cancer and further envisage the promising application of FGFR2 in gastric cancer targeted therapy. Fibroblast growth factor signals & fibroblast growth factor receptor family
FGFs are involved in fetal morphogenesis, adult tissue homeostasis and tumorigenesis [6]. FGFs play important roles in a variety of cellular processes, such as cell proliferation, stemness, apoptosis, angiogenesis and drug resistance [7]. The secreted-type ligands of the FGF family, including FGF1–10 and FGF16– 23, bind to multiple FGFRs to transduce signals in target cells. FGF triggers the autophosphorylation of FGFR, which results in a structural change of the tyrosine kinase domain, thus phosphorylating other tyrosine residues at substrate-binding sites along with FGFR-bound adaptor molecules. FGF signals will induce the activation of RAS-ERK, PI3KAKT, DAG-PKC/PKD signaling cascade and IP3-mediated Ca2+ release [8]. FGF signaling cascades interact with Notch, WNT, Hedgehog and BMP signaling cascades to maintain the homeostasis among stem and progenitor cells [9]. The FGFR family comprises four tyrosine kinase receptors: FGFR1, 2, 3, 4 [10]. They
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share a common domain architecture consisting of extracellular immunoglobulin-like domains and cytoplasmic tyrosine kinase domain. FGFR genes are proto-oncogenes activated in human cancers as a result of gene amplification, chromosomal translocation and point mutation [4]. FGFR2 gene, located at human chromosome 10q26, is characterized by its amplification and overexpression in the diffuse-type gastric cancer [11]. FGFR2 is regulated on the basis of the balance of FGFs, heparan-sulfate proteoglycans, FGFR2 isoforms and endogenous inhibitors [12]. FGFR2b and FGFR2c are FGFR2 isoforms [13]. FGFR2b isoform, consisting of exons 1–6, 8, 9, 11–19 and 21, is predominantly expressed in epithelial cells. FGFR2c isoform, consisting of exons 1–6, 8, 10–19 and 21, is preferentially in mesenchymal cells. FGFR2b functions as the receptor for FGF1, FGF3, FGF7, FGF10 and FGF22, while FGFR2c for FGF1, FGF2, FGF4, FGF6, FGF9, FGF16 and FGF20. Activation of FGFR2b and FGFR2c will result in ligand-independent FGF signaling, thus playing important roles in the development of diffuse-type gastric cancer (FIGURE 1). Expression of FGFR2 in gastric cancer
Yamashita et al. have found that diffuse-type gastric cancer harbors aberrations in the FGFR2/ErbB3/PI3 kinase pathway, while intestinal-type gastric cancer has an activated ErbB2 oncogenic pathway [14]. Guo et al. have found that almost all intestinal-type gastric cancer tumors overexpressed at least one of a panel of three proteins, MET, FGFR2 and EPHA2 [15]. Matsumoto et al. have found that FGFR2 amplification was observed in 4.1% (11 out of 267) of gastric cancers [16]. No amplification of the three other FGFR family members (FGFR1, 3 and 4) was detected. A FISH analysis was performed on 7 cases among 11 FGFR2-amplified cases and showed that 6 of these 7 cases were highly amplified, while the remaining 1 had a relatively low grade of amplification. Although the difference was not significant, patients with FGFR2 amplification tended to exhibit a shorter overall survival period. Kim et al. have found that the combined Diffuse-type gastric cancer
FGF
FGFR2 amplification
FGF signals
RAS-ERK
PI3K-AKT
DAG-PKC/PKD
IP3–Ca2+ release
Regulation of cell growth, apoptosis, drug resistance
Figure 1. FGF signalling in diffuse-type gastric cancer. FGFR2: FGF receptor 2.
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expression of MYC, EGFR and FGFR2 was predictive of poor survival in cisplatin and 5-fluorouracil (5-FU)-treated metastatic gastric cancer patients [17]. The FGFR2 gene is homologous to other genes, including K-sam and KGFR [18]. Overexpression of FGFR2/K-sam is correlated with poor prognosis in gastric cancer. Hattori et al. have examined the expression of the FGFR2/K-sam protein in 38 cases of gastric cancer by immunohistochemistry [18]. Totally 20 cases (52.63%) of the undifferentiated type of advanced gastric cancer were K-sam positive. The K-sam protein was detected only focally in the primary tumor, with strong staining in the metastasized tumor in the lymph node and liver. Toyokawa et al. have found that the prognosis of K-sampositive gastric cancer patients was significantly poorer than that of K-sam-negative patients [19]. Genetic variations, especially single nucleotide polymorphisms (SNPs), are involved in the functional activation of FGFR2 protein during carcinogenesis. SNPs of the FGFR2 gene are associated with an increased risk of estrogen receptor-positive breast cancer [20]. The association between SNPs of the FGFR2 gene and diffuse-type gastric cancer remains unknown. Katoh has reported that gain-of-function mutations or variations of FGFR2 occurred in estrogen receptor-positive breast cancer, diffuse-type gastric cancer and endometrial uterine cancer [21]. Jang et al. have reported two identical mutations in FGFR2 that caused craniosynostosis syndromes, Crouzon, Apert and Pfeiffer syndromes in gastric carcinoma [22]. A missense mutation (Ser267Pro) in exon IIIa and a splice site mutation (940-2A–>G) in exon IIIc were detected in gastric cancer patients. Functions & mechanism of FGFR2 in gastric cancer
Inhibitors of FGFR2 may have therapeutic efficacy in the subset of gastric cancers containing FGFR2 amplification (TABLE 1). Kunii et al. have found that FGFR2-amplified gastric cancer cell lines required FGFR2 and Erbb3 signaling for growth and survival [23]. FGFR2 was overexpressed and tyrosine phosphorylated selectively in FGFR2-amplified gastric cancer cell lines KATOIII, SNU-16 and OCUM-2M. Inhibition of FGFR2 kinase by a specific small-molecule inhibitor, PD173074, resulted in growth inhibition and cell cycle arrest in KATO-III cells, and induced apoptosis in both SNU-16 and OCUM-2M cells. In FGFR2-amplified gastric cancer cell lines, the elevated expression of EGFR, Her2 and Erbb3 phosphotyrosine was dependent on FGFR2, revealing that EGFR family kinases were downstream targets of amplified FGFR2. Matsumoto et al. have found that FGFR2 amplification could confer hypersensitivity to FGFR inhibitor in gastric cancer cell lines [16]. Park et al. have found that the epigenetic silencing of FGFR2 through DNA methylation might play important roles in gastric carcinogenesis [24]. The restoration of FGFR2 expression by treating methylated gastric cancer cells with the DNA methyltransferase inhibitor 5-aza2´-deoxycytidine strongly suggested that the loss of FGFR2 expression might be due to the aberrant hypermethylation in the promoter region of the FGFR2 gene. Expert Rev. Gastroenterol. Hepatol. 7(8), (2013)
FGFR2 & gastric cancer
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Table 1. The role of anti-FGF receptor 2 agents in gastric cancer. Agent
Type
Method
Effect
PD173074
Preclinical
In vitro
Induce growth inhibition and apoptosis of gastric cancer cells
[23]
AZD2171
Preclinical
In vitro/vivo
Induce growth inhibition of gastric cancer cells
[25]
AZD4547
Preclinical
In vitro/vivo
Induce growth inhibition and apoptosis of gastric cancer cells
[26]
S49076
Preclinical
In vitro/vivo
Inhibit growth and reverse drug resistance of gastric cancer cells
[27]
GP369
Preclinical
In vitro/vivo
Induce growth inhibition of gastric cancer cells
[28]
Ki23057
Preclinical
In vitro/vivo
Inhibit growth and reverse drug resistance of gastric cancer cells
[30]
Brivanib
Phase I trial
Clinical trial
Brivanib plus cetuximab lead to 9.7% response of gastrointestinal patients
[33]
AZD2171 completely inhibits the phosphorylation of FGFR2 and downstream signaling proteins, such as FRS2, AKT and mitogen-activated protein kinase [25]. AZD2171 also inhibits other receptor tyrosine kinases, such as PDGFRA, PDGFRB, KIT, VEGFR1, VEFGR2 and VEGFR3. AZD2171 can directly inhibit the growth of two gastric cancer cell lines KATO-III and OCUM-2M, which overexpress FGFR2 [25]. Oral administration of AZD2171 can significantly and dosedependently inhibit in vivo proliferation of cancer cells with aberrant FGFR2 activation in rodent therapeutic models. AZD4547 effectively inhibits the phosphorylation of FGFR2 [26]. Xie et al. have found that FGFR2 gene amplification in gastric cancer could predict sensitivity to AZD4547 [26]. The gastric cancer cell lines carrying the amplified FGFR2 gene, SNU-16 and KATO-III, were extremely sensitive to AZD4547 in vitro. AZD4547 could effectively induce apoptosis of SNU-16 cells by inhibiting the downstream signaling molecules of FGFR2. Furthermore, inhibition of FGFR2 signaling by AZD4547 resulted in significant dose-dependent tumor growth inhibition in FGFR2-amplified xenograft and patient-derived gastric cancer xenograft models, but not in non-amplified models. shRNA knockdown of FGFR2 led to similar inhibition of tumor growth in vitro and in vivo. Comparing with monotherapy, AZD4547 in combination with chemotherapeutic agents showed enhancement of in vivo anti-tumor efficacy. Taken together, FGFR2 pathway activation was required for driving growth and survival of gastric cancer carrying FGFR2 gene amplification both in vitro and in vivo. Burbridge et al. have described the preclinical characterization of S49076, a novel inhibitor of FGFR2 [27]. S49076 could also potently block cellular phosphorylation of MET, AXL/MER, FGFR1, FGFR3 and inhibited downstream signaling in vitro and in vivo. In cell models, S49076 inhibited the proliferation of FGFR2-dependent gastric cancer cells, and inhibited colony formation of hepatocarcinoma cells expressing FGFR1/2 and AXL. In tumor xenograft models, oral administration of S49076 could significantly inhibit tumor growth. FGFRs have been implicated in resistance to VEGF/VEGFR inhibitors, such as bevacizumab. S49076 alone could induce tumor growth arrest in bevacizumab-resistant tumors. Moreover, combination www.expert-reviews.com
Ref.
of S49076 with bevacizumab in cancer xenograft models led to near total inhibition of tumor growth. Dysregulated FGFR2 signaling is one of the critical oncogenic pathways involved in the initiation and/or maintenance of tumors. Bai et al. have found that GP369, an FGFR2-IIIb-specific antibody, could exhibit potent antitumor activity against gastric cancers driven by activated FGFR2 signaling [28]. They discovered that gastric cancer cell lines harboring FGFR2 amplification predominantly expressed the IIIb isoform of the receptor. GP369 could specifically and potently suppress ligand-induced phosphorylation of FGFR2-IIIb and downstream signaling, as well as FGFR2-driven proliferation in vitro. The administration of GP369 in mice could significantly inhibit the growth of human cancer xenografts harboring activated FGFR2 signaling. Thus, cancer patients with aberrantly activated/amplified FGFR2 signaling could potentially benefit from therapeutic intervention with FGFR2-targeting antibodies. Scirrhous gastric carcinoma carries the highest mortality because of a frequent metastasis to lymph node. A FGFR2 phosphorylation inhibitor or TGFbetaR inhibitor appears therapeutically promising in scirrhous gastric carcinoma [29]. Yashiro et al. have found that a FGFR2 phosphorylation inhibitor could prolong the survival of mice with peritoneal metastasis of scirrhous gastric cancer. Nakamura et al. have found that the FGFR2 phosphorylation inhibitor, Ki23057, appeared therapeutically promising in scirrhous gastric carcinoma [30]. Ki23057 could significantly inhibit the proliferation of scirrhous cancer cells but not non-scirrhous gastric carcinoma cells. The oral administration of Ki23057 could significantly prolong survival of mice with injection of OCUM-2MD3 scirrhous cancer cells. Kataoka et al. have found that foretinib, an oral multikinase inhibitor known to target MET, RON, AXL and vascular endothelial growth factor receptors, could effectively inhibit the growth of gastric cancer cells harboring not only MET but also FGFR2 amplification by blocking inter-RTK signaling networks [31]. Pan et al. have found that MK-2461, a novel ATP-competitive multitargeted inhibitor of activated c-Met, displayed significant inhibitory activities against FGFR [32]. 761
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Brivanib is an oral dual inhibitor of FGFR and VEGFR signaling pathways. Garrett et al. have performed a Phase I study to determine the safety and efficacy of brivanib combined with cetuximab in patients with advanced gastrointestinal malignancies [33]. The most common treatment-related toxicities were fatigue, diarrhea and anorexia. A total of 62 patients received brivanib (320, 600 or 800 mg daily) plus cetuximab (400 mg/ m2 loading dose then 250 mg/m2 weekly), and 6 (9.7%) patients had objective radiographic partial responses. The median duration of response and median progression-free survival was 9.2 and 3.9 months, respectively. Park et al. have carried out a Phase II study of brivanib as first-line therapy in patients with advanced hepatocellular carcinoma [34]. Brivanib demonstrated promising antitumor activity and a manageable safety profile in 55 cases of patients. Brivanib was generally well tolerated, and the 6-month progression-free survival rate was 18.2%. Ponatinib (AP24534) is an oral multitargeted kinase inhibitor that potently inhibits the in vitro kinase activity of all four members of the FGFR family [35]. In a panel of 14 cell lines representing various tumor types, including gastric cancer, ponatinib can inhibit FGFR-mediated signaling and inhibited cell growth. Daily oral dosing of ponatinib (10–30 mg/kg) to mice reduced tumor growth and inhibited signaling in all three tumor models examined. Gozgit et al. have found that combined targeting of FGFR2 and mTOR by ponatinib and ridaforolimus results in synergistic antitumor activity in FGFR2 mutant endometrial cancer models [36]. LY2874455 is also a potent inhibitor of all four members of the FGFR family [37]. LY2874455 exhibits a potent activity against FGF/ FGFR-mediated signaling in gastric cancer cell lines, and shows anti-tumor activity in gastric cancer xenograft models. Effect of FGFR2 on drug resistance of gastric cancer cells
Drug resistance is a big obstacle for gastric cancer therapy [38]. FGFR inhibitors can enhance the sensitivity to conventional anticancer drugs, such as 5-FU, irinotecan, paclitaxel and etoposide, in human cancer cells with aberrant FGFR activation [39]. Because there are multiple mechanisms of action for FGFR inhibitors to overcome drug resistance in human cancer, FGFR-targeted therapy is a promising strategy for the treatment of drug-resistant gastric cancer. Ki23057 is a broad-range tyrosine kinase inhibitor, inhibiting FGFR1, FGFR2 and VEGF2 tyrosine kinases. Qiu et al. have found that Ki23057 could enhance the chemosensitivity of drug-resistant gastric cancer cells, especially when used in combination with irinotecan, paclitaxel or etoposide [40]. The effects of the combination of Ki23057 with anticancer drugs on proliferation and apoptosis were examined in five gastric cancer cells with resistance to irinotecan, paclitaxel, etoposide, oxaliplatin and gemcitabine, respectively. Ki23057 could significantly enhance the apoptosis rates induced by chemotherapeutic drugs in both the drug-resistant cell lines and the parental cell line. Ki23057 could significantly decrease the IC50 values 762
of cancer cells resistant to irinotecan, paclitaxel or etoposide, but not the cells resistant to oxaliplatin, and gemcitabine. Ki23057 could decrease the ERCC1 expression level and increase the p53 expression level in the cancer cells resistant to irinotecan, paclitaxel or etoposide, indicating that ERCC1 and p53 may play an integral role in the synergism between Ki23057 and chemotherapeutic agents. Yashiro et al. have found the combined treatment with 5-FU and Ki23057 produced synergistic anti-tumor effects for scirrhous gastric cancer treatment [41]. Ki23057 at 100 nM could significantly inhibit the proliferation and decrease the phosphorylation of FGFR2 in scirrhous gastric cancer cells, but not in nonscirrhous gastric cancer cells. The combination of Ki23057 and 5-FU showed synergistic antitumor effects for scirrhous gastric cancer cells by decreasing DPD expression and increasing p21 expression. The combined administration of Ki23057and S1 could significantly decrease the growth of orthotopic tumors and lymph node metastasis more effectively than S1 alone. Expert commentary
Gastric cancer is one of most common malignancies in the world. Despite a reduction in mortality, gastric cancer still represents a leading cause of death worldwide. Recently, more and more studies have investigated the therapeutic value of molecularly targeted agents in gastric cancer [42]. Since FGF signaling is involved in various aspects of cancer biology, FGFR-targeted therapy is an active topic in the field of clinical oncology. FGFR2 overexpression or mutation is significantly related with diffuse types of gastric cancer. Inhibitors of FGFR2 can significantly inhibit the proliferation of gastric cancer cells with FGFR2 mutation or gene amplification. FGFR inhibitors can also overcome the drug resistance of gastric cancer cells. Furthermore, inhibitors of FGFR2 show synergistic anti-tumor effects for gastric cancer cells in combination with chemotherapeutic drugs. Thus, FGFR2 is considered as an important target for gastric cancer treatment. The use of FGFR2 inhibitors for therapy of gastric cancer patients with FGFR2 mutation or gene amplification is a promising strategy. Since the inhibitors of FGFR2 have demonstrated encouraging efficacy in early phase trials, future treatment options for gastric cancer appear bright. However, many questions remain to be answered: What is the relation between FGFR2 SNPs and risk of diffuse-type gastric cancer? What is the mechanism of FGFR2 in drug resistance of gastric cancer? How to select the right set of patients that can benefit from anti-FGFR2 therapy? What is the side effect of anti-FGFR2 therapy? More in vivo assay and clinical trials are needed to evaluate the effect of combined therapy of anti-FGFR2 inhibitors and traditional therapeutic drugs. Five-year view
Although the FGFR2-based therapy seems to have a potential role in gastric cancer patients, the results of more clinical trials are still pending. More investigations should be performed along the following avenues that are likely to lead to exciting results. Expert Rev. Gastroenterol. Hepatol. 7(8), (2013)
FGFR2 & gastric cancer
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Identification of the mechanisms of FGFR2 in gastric cancer
There is diversity of molecular changes acquired during gastric carcinogenesis [43]. FGFR2-related FGF signaling cascades play an important role in gastric carcinogenesis through regulation of cancer stem cells, cell proliferation, apoptosis and angiogenesis. In different gastric cancer cells, FGFR2 can regulate diverse pathways. Continued basic studies are warranted to gain more insights into the molecular mechanisms of FGFR2 in cancer development and progression. Understanding the regulatory network of FGFR2 in drug resistance of gastric cancer will lead to possible improvements in personalized therapeutics. Characterization of FGFR2-induced critical alterations will help to find novel therapeutic targets for gastric cancer. Identification of the biomarkers of FGFR2-based therapy
The inhibitors of FGFR are promising anticancer drugs for certain diffuse-type gastric cancer patients carrying FGFR2 gene amplification. A great challenge is the identification of biomarkers that can help to select the right patient candidate to FGFR2-based therapy. FISH analyses, utilized for the detection of gene amplification of FGFR2, can be used to facilitate patient selection. Immunohistochemistry can also be used to detect the expression of FGFR2 in normal gastric tissues [44] and gastric cancer tissues [45]. Analysis of SNPs or copy number polymorphism (CNP) in FGF signaling genes will give information on the sensitivity to FGFR2-based therapy. Whole exome/ transcriptome sequencing will play a crucial role to identify the right patient population in the era of personalized medicine. Identification of the side effects of FGFR2-based therapy
Since dysregulation of FGFR2 signaling is involved in both cancer and congenital disorders [46], the safety of FGFR2-based
Review
therapy should be carefully evaluated before future clinical application. Tyrosine kinase inhibitors, human antibody, peptide mimetic and siRNA are potential technologies to be applied for anti-FGFR2 therapy. The long-term safety of these anti-FGFR2 inhibitors need to be investigated in animal models. An ideal anti-FGFR2 inhibitor will lead to the effective therapeutic outcomes without any unanticipated side effects. It is also necessary to investigate the toxicity resulting from the addition of anti-FGFR2 agents to traditional cytotoxic chemotherapy. Identification of the strategy of combination therapy
Monotherapy with anti-FGFR2 inhibitors may be less toxic, but less efficient either. Anti-FGFR2 inhibitors can decrease the drug resistance of cancer cells, thus improving the efficacy of current chemotherapeutic drugs. In order to improve the efficacy of single-agent therapy, further studies will be required to establish the most effective combinations of anti-FGFR2 inhibitors and other drugs with minimal side effect. The combination of FGFR2 targeted agents with chemotherapeutic drugs based on a patient’s molecular profile may deliver better responses. Financial & competing interests disclosure
This study was supported in part by grants from the National Natural Scientific Foundation of China (81100714, 81171923), the Foundation of Shaanxi Province Science and Technology research (2012KJXX-20) and the Top PhD Foundation of China (201075). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues • Gastric cancer remains a leading cause of death worldwide, and effective target therapy is urgently needed. • FGF receptor 2 (FGFR2) is preferentially amplified and overexpressed in the diffuse-type gastric cancer. • Inhibitors of FGFR2 can induce growth inhibition, apoptosis and drug sensitivity of gastric cancer cells in vitro and in vivo. • Inhibitors of FGFR2 show synergistic anti-tumor effects for gastric cancer cells in combination with chemotherapeutic drugs. • FGFR2 is considered as one valuable target for gastric cancer treatment. • More clinical trials should be performed to promote the use of FGFR2 in clinic.
References
3
Yasui W, Sentani K, Sakamoto N, Anami K, Naito Y, Oue N. Molecular pathology of gastric cancer: research and practice. Pathol. Res. Pract. 207(10), 608–612 (2011).
6
Kumar SB, Narasu L, Gundla R, Dayam R, J A R P S. Fibroblast growth factor receptor inhibitors. Curr. Pharm. Des. 19(4), 687–701 (2013).
4
Katoh Y, Katoh M. FGFR2-related pathogenesis and FGFR2-targeted therapeutics. Int. J. Mol. Med. 23(3), 307–311 (2009).
7
5
Katoh M, Katoh M. FGF signaling network in the gastrointestinal tract. Int. J. Oncol. 29(1), 163–168 (2006).
Brooks AN, Kilgour E, Smith PD. Molecular pathways: fibroblast growth factor signaling: a new therapeutic opportunity in cancer. Clin. Cancer Res. 18(7), 1855–1862 (2012).
8
Katoh M, Nakagama H. FGF receptors: cancer biology and therapeutics. Med. Res.
Papers of special note have been highlighted as: • of interest •• of considerable interest 1
Smyth EC, Cunningham D. Targeted therapy for gastric cancer. Curr. Treat. Options. Oncol. 13(3), 377–389 (2012).
2
De Vita F, Giuliani F, Silvestris N et al. Current status of targeted therapies in advanced gastric cancer. Expert. Opin. Ther. Targets 16(Suppl. 16), S29–S34 (2012).
www.expert-reviews.com
763
Review
Hong, Han, Liu & Brain
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by V U L Periodicals Rec on 12/28/14 For personal use only.
Rev. doi:10.1002/med.21288 (2013) (Epub ahead of print). ••
An overview of FGF receptors (FGFRs) in cancer therapy.
9
Katoh M. Cancer genomics and genetics of FGFR2 (Review). Int. J. Oncol. 33(2), 233–237 (2008).
10
Katoh M. FGFR2 abnormalities underlie a spectrum of bone, skin, and cancer pathologies. J. Invest. Dermatol. 129(8), 1861–1867 (2009).
11
12
13
14
15
16
Katoh M, Katoh M. Recombination cluster around FGFR2-WDR11-HTPAPL locus on human chromosome 10q26. Int. J. Mol. Med. 11(5), 579–583 (2003). Xu R, Rudd TR, Hughes AJ, Siligardi G, Fernig DG, Yates EA. Analysis of the fibroblast growth factor receptor (FGFR) signalling network with heparin as coreceptor: evidence for the expansion of the core FGFR signalling network. FEBS J. 280(10), 2260–2270 (2013). Christensen C, Berezin V, Bock E. Neural cell adhesion molecule differentially interacts with isoforms of the fibroblast growth factor receptor. Neuroreport 22(15), 727–732 (2011). Yamashita K, Sakuramoto S, Watanabe M. Genomic and epigenetic profiles of gastric cancer: potential diagnostic and therapeutic applications. Surg. Today 41(1), 24–38 (2011). Guo T, Fan L, Ng WH et al. Multidimensional Identification of Tissue Biomarkers of Gastric Cancer. J Proteome Res. (2012) (Epub ahead of print).
Rev. Anticancer Ther. 10(9), 1375–1379 (2010). 21
22
Garrett CR, Siu LL, El-Khoueiry A et al. Phase I dose-escalation study to determine the safety, pharmacokinetics and pharmacodynamics of brivanib alaninate in combination with full-dose cetuximab in patients with advanced gastrointestinal malignancies who have failed prior therapy. Br. J. Cancer 105(1), 44–52 (2011).
•
Park S, Kim JH, Jang JH. Aberrant hypermethylation of the FGFR2 gene in human gastric cancer cell lines. Biochem. Biophys. Res. Commun. 357(4), 1011–1015 (2007).
A clinical trial of brivanib plus cetuximab in patients with advanced gastrointestinal malignancies.
34
Takeda M, Arao T, Yokote H et al. AZD2171 shows potent antitumor activity against gastric cancer over-expressing fibroblast growth factor receptor 2/ keratinocyte growth factor receptor. Clin. Cancer Res. 13(10), 3051–3057 (2007).
Park JW, Finn RS, Kim JS et al. Phase II, open-label study of brivanib as first-line therapy in patients with advanced hepatocellular carcinoma. Clin. Cancer Res. 17(7), 1973–83 (2011).
35
Xie L, Su X, Zhang L et al. FGFR2 gene amplification in gastric cancer predicts sensitivity to the selective FGFR inhibitor AZD4547. Clin. Cancer Res. 19(9), 2572–2583 (2013).
Gozgit JM, Wong MJ, Moran L et al. Ponatinib (AP24534), a multitargeted pan-FGFR inhibitor with activity in multiple FGFR-amplified or mutated cancer models. Mol. Cancer Ther. 11(3), 690–699 (2012).
36
Gozgit JM, Squillace RM, Wongchenko MJ et al. Combined targeting of FGFR2 and mTOR by ponatinib and ridaforolimus results in synergistic antitumor activity in FGFR2 mutant endometrial cancer models. Cancer Chemother. Pharmacol. 71(5), 1315–1323 (2013).
37
Zhao G, Li WY, Chen D et al. A novel, selective inhibitor of fibroblast growth factor receptors that shows a potent broad spectrum of antitumor activity in several tumor xenograft models. Mol. Cancer Ther. 10(11), 2200–2210 (2012).
38
Yashiro M, Chung YS, Nishimura S, Inoue T, Sowa M. Peritoneal metastatic model for human scirrhous gastric carcinoma in nude mice. Clin. Exp. Metastasis. 14(1), 43–54 (1996).
Zhang D, Fan D. New insights into the mechanisms of gastric cancer multidrug resistance and future perspectives. Future Oncol. 6(4), 527–537 (2010).
39
Nakamura K, Yashiro M, Matsuoka T et al. A novel molecular targeting compound as K-samII/FGF-R2 phosphorylation inhibitor, Ki23057, for Scirrhous gastric cancer. Gastroenterology 131(5), 1530–1541 (2006).
Chaffer CL, Dopheide B, Savagner P, Thompson EW, Williams ED. Aberrant fibroblast growth factor receptor signaling in bladder and other cancers. Differentiation 75(9), 831–842 (2007).
40
Qiu H, Yashiro M, Zhang X, Miwa A, Hirakawa K. A FGFR2 inhibitor, Ki23057, enhances the chemosensitivity of drug-resistant gastric cancer cells. Cancer Lett. 307(1), 47–52 (2011).
25
26
27
18
Hattori Y, Itoh H, Uchino S, Hosokawa K et al. Immunohistochemical detection of K-sam protein in stomach cancer. Clin. Cancer Res. 2(8), 1373–1381 (1996).
29
Toyokawa T, Yashiro M, Hirakawa K. Co-expression of keratinocyte growth factor and K-sam is an independent prognostic factor in gastric carcinoma. Oncol. Rep. 21(4), 875–880 (2009).
30
764
33
24
Matsumoto K, Arao T, Hamaguchi T et al. FGFR2 gene amplification and clinicopathological features in gastric cancer. Br. J. Cancer. 106(4), 727–732 (2012).
Katoh M. Genetic alterations of FGF receptors: an emerging field in clinical cancer diagnostics and therapeutics. Expert
Pan BS, Chan GK, Chenard M et al. MK2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 70(4), 1524–1533 (2010).
Kunii K, Davis L, Gorenstein J et al. FGFR2-amplified gastric cancer cell lines require FGFR2 and Erbb3 signaling for growth and survival. Cancer Res. 68(7), 2340–2348 (2008).
Kim HK, Choi IJ, Kim CG et al. Three-gene predictor of clinical outcome for gastric cancer patients treated with chemotherapy. Pharmacogenomics J. 12(2), 119–127 (2012).
20
Jang JH, Shin KH, Park JG. Mutations in fibroblast growth factor receptor 2 and fibroblast growth factor receptor 3 genes associated with human gastric and colorectal cancers. Cancer Res. 61(9), 3541–3543 (2001).
32
23
17
19
Katoh M. Dysregulation of stem cell signaling network due to germline mutation, SNP, Helicobacter pylori infection, epigenetic change and genetic alteration in gastric cancer. Cancer Biol. Ther. 6(6), 832–839 (2007).
inhibitor of MET and VEGFRs, inhibits growth of gastric cancer cell lines by blocking inter-receptor tyrosine kinase networks. Invest. New Drugs 30(4), 1352–1360 (2012).
28
31
Burbridge MF, Bossard CJ, Saunier C et al. S49076 is a novel kinase inhibitor of MET, AXL and FGFR with strong preclinical activity alone and in association with bevacizumab. Mol. Cancer Ther. (2013) (Epub ahead of print). Bai A, Meetze K, Vo NY et al. GP369, an FGFR2-IIIb-specific antibody, exhibits potent antitumor activity against human cancers driven by activated FGFR2 signaling. Cancer Res. 70(19), 7630–7639 (2010).
Kataoka Y, Mukohara T, Tomioka H et al. Foretinib (GSK1363089), a multi-kinase
Expert Rev. Gastroenterol. Hepatol. 7(8), (2013)
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by V U L Periodicals Rec on 12/28/14 For personal use only.
FGFR2 & gastric cancer
41
Yashiro M, Shinto O, Nakamura K et al. Synergistic antitumor effects of FGFR2 inhibitor with 5-fluorouracil on scirrhous gastric carcinoma. Int. J. Cancer 126(4), 1004–1016 (2010).
42
Asaoka Y, Ikenoue T, Koike K. New targeted therapies for gastric cancer. Expert Opin. Investig. Drugs 20(5), 595–604 (2011).
•
A review of targeted therapies in gastric cancer.
www.expert-reviews.com
43
Deng N, Goh LK, Wang H et al. A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut 61(5), 673–684 (2012).
44
Hughes SE. Differential expression of the fibroblast growth factor receptor (FGFR) multigene family in normal human adult tissues. J. Histochem. Cytochem. 45(7), 1005–1019 (1997).
Review
45
La Rosa S, Uccella S, Erba S et al. Immunohistochemical detection of fibroblast growth factor receptors in normal endocrine cells and related tumors of the digestive system. Appl. Immunohistochem. Mol. Morphol. 9(4), 319–328 (2001).
46
Katoh M, Katoh M. FGFR2 and WDR11 are neighboring oncogene and tumor suppressor gene on human chromosome 10q26. Int. J. Oncol. 22(5), 1155–1159 (2003).
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