YEAR IN REVIEW LUNG CANCER IN 2014
to the IL‑6/JAK1/STAT3 axis, STAT3 is also activated downstream of FGFR through PI3K (Figure 1). Lee and co-workers2 cotreated PC-9 cells with erlotinib and the FGFR inhibitor PD 173074 and/or the JAK inhibitor ruxolitinib. Although inhibition with each agent partially blocked erlotinibinduced STAT3 phosphorylation, combining both inhibitors completely suppressed STAT3 induction. These findings were expanded to other oncogene-addicted cancer cells, revealing a common cancer protective feedback mechanism triggered by MEKpathway inhibition.2 These data show that only by blocking all STAT3 feedback pathway mechanisms using drug combinations can we start to circumvent therapeutic resistance. Also in 2014, Hachemi et al. 5 showed that 18F‑FDG-PET–CT could be a useful clinical tool for early evaluation of targeted therapies. This study highlighted the value of 18F‑FDG-PET–CT as a means to monitor response to targeted therapies that do not induce rapid tumour shrinkage.5 A decrease in maximum standardized uptake value (SUV) of at least 21.6% soon after starting therapy could discriminate progressive disease from nonprogressive disease in patients, and was correlated with improved progression-free survival (PFS) and overall survival.5 However, 18F‑FDG-PET–CT might not detect cells that escape adaptive changes in response to therapeutic pressure. The
Optimizing lung cancer treatment approaches Rafael Rosell and Niki Karachaliou
In 2014, developments in our understanding of escape signalling circuits implicated in resistance to targeted agents in patients with lung cancer have led to improvements in tackling such resistance. The potential role for PET in the management of erlotinib therapy, novel combination therapies and pharmacogenomic-driven individualization of platinum‑based chemotherapy represent other key advances. Rosell, R. & Karachaliou, N. Nat. Rev. Clin. Oncol. advance online publication 23 December 2014; doi:10.1038/nrclinonc.2014.225
Great strides have been made in lung cancer therapy, but a cure remains elusive for the vast majority of patients. The high death toll from lung cancer and unsatisfactory results of treatment have spurred us to improve our understanding of the molecular basis of this disease. EGFR mutations are among the most-common driver mutations, and tumours with these aberrations respond well to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib or erlotinib, although these responses are often transient owing to drug resistance.1 One mechanism of drug resist ance to EGFR therapy is the T790M gatekeeper mutation within EGFR. A second mechanism is activation of alternative receptor tyrosine kinases that maintain signal ling via key downstream pathways despite sustained inhibition of EGFR.1 In 2014, studies that unravel some of the genetic alterations have enhanced progress in the field. In particular, Lee et al.2 noted that erlotinib increased phosphorylation of STAT3 via feedback mechanisms involving IL-6 and FGF in almost all tested lung cancer cell lines that harboured EGFR mutations, but did not affect phosphorylated STAT3 in EGFR wildtype cells. Activated STAT3 regulates tumour growth, invasion, proliferation, angiogenesis, immune response, and metabolic reprogramming, and therefore its activation enables the tumour to survive pressure caused by targeted therapies. Thus, STAT3 activation following erlotinib treatment represents an undervalued and deleterious response, and a better understanding of this effect could help circumvent mechanisms of resistance to EGFR TKIs.
Previous studies had shown that constitutively activated mutant EGFRs promoted the production and release of IL‑6, which signals through the gp130 common cytokine receptor signalling subunit and the Janus kinases (JAKs), leading to STAT3 phosphorylation.3 Paradoxically, erlotinib had been shown to induce MET-independent activation of STAT3 signalling in EGFR-mutant lung cancer cells.4 To identify upstream activators of STAT3, Lee et al.2 performed global gene-expression analysis in four EGFRmutant cell lines and found that 243 genes were upregulated by erlotinib, and demon strated a direct connection between the FGFR2/3 and STAT3 pathways. In addition
TGF-β
EGF
EGFR del19 L858R P T790M PI3K
AKT
P
RAS
P
RAF
TGF-βR
IL-6
FGF
IL-6R
FGFR2/3 FRS2
EGFR TKIs
JAK1/2
STAT3
JAK1/2
P
MEK1/2
STAT3
PI3K P
STAT3
P
VEGF
Figure 1 | Imbalance in EGFR-mutant signalling networks caused by single-agent TKI therapy. EGFR Nature Reviews | and Clinical Oncology TKIs induce activation of STAT3 through autocrine upregulation of the IL‑6–IL‑6R FGF–FGFR2/3 pathways.2 Activation of the RAS/RAF/MEK/ERK pathway downstream of EGFR is prevented by EGFR TKIs, whereas STAT3 is paradoxically hyperactivated via the IL-6R/JAK1/2/STAT3 axis. TGF‑β can also induce IL‑6 axis activation. Expression of FGFR2/3 is markedly increased in response to EGFR TKIs and activates STAT3 through PI3K. These mechanisms probably underlie resistance to these agents, which could potentially be overcome through combination therapy.
NATURE REVIEWS | CLINICAL ONCOLOGY
ADVANCE ONLINE PUBLICATION | 1 © 2014 Macmillan Publishers Limited. All rights reserved
YEAR IN REVIEW Key advances ■■ EGFR-inhibitor treatment of EGFR-mutant NSCLC leads to STAT3 activity, promoting disease progression; EGFR inhibition combined with FGFR/PI3K plus JAK inhibition or direct STAT3 inhibition blocks this pathway2,7 ■■ The clinical benefit of EGFR inhibitors combined with VEGF-targeted therapies paves the way to use combination therapy to improve outcomes in patients with EGFR-mutant NSCLC6 ■■ Academic initiatives such as the cooperative Chinese–European BREC studies to overcome the limited efficacy of platinum-based chemotherapy in patients with advanced-stage NSCLC should be strongly supported9
authors comment that one limitation was the lack of an established SUV cut-off to discriminate patients with metabolic progression from nonmetabolic progression, as well as establishing a reliable SUV cut-off.5 The senescence-related ‘reverse Warburg’ cell state compensates for the weakness of both RECIST and FDG-PET for evaluation of response to new targeted therapies. Until we have a more-appropriate imaging tool to assess response to targeted therapies, early changes in 18F‑FDG uptake can predict PFS, survival and response in NSCLC patients within 2 weeks of erlotinib treatment.5 This year, Seto et al.6 published a phase II randomized study in patients with EGFR mutant NSCLC that examined the potential benefit of adding bevacizumab to erlotinib, compared with erlotinib alone. This study represents a novel therapeutic approach for optimizing treatment and might pave the way for combination therapy to improve outcomes in EGFR-mutant NSCLC. Important differences in PFS were observed in patients receiving combined treatment, with an almost twofold increase in duration of PFS from 9.7 months for erlotinib alone to 16 months for erlotinib plus bevacizumab (P = 0.0015), a new landmark in the treatment of this disease.6 Although the authors suggested that the benefit of bevacizumab could be related partly to its antiangiogenic effect in normalizing the tumour vasculature and potentially enhancing access of erlotinib to the tumour, it is plausible that inhibition of VEGF signalling by bevacizumab could also contribute to attenuating induction of STAT3 phosphorylation by erlotinib.7 Nintedanib is an oral angiokinase inhi bitor that simultaneously targets multiple proangiogenic pathways mediated by VEGFR1–3, FGFR1–3, and PDGFRα and
PDGFRβ. The results of the LUME-Lung 1 trial,8 in which patients with NSCLC were randomized to second-line docetaxel plus placebo or docetaxel plus nintetanib, provided further support for this approach. Nintedanib plus docetaxel significantly improved PFS in the total study population (median 3.4 months versus 2.7 months, P = 0.0019), and overall survival was prolonged in patients with adenocarcinoma (median 12.6 months versus 10.3 months, P = 0.0359).8 Despite lacking genomic profiling or biomarker assessments, this trial has contributed greatly to improving second-line therapy for advanced-stage NSCLC. Platinum-based chemotherapy remains the cornerstone of treatment for most patients with advanced-stage NSCLC and any effort to customize chemotherapy remains of great relevance. In a global academic collaborative effort without any industry funding, the BRCA1-RAP80 Expression Customization (BREC) studies investigated an approach to increase the efficacy of cisplatin by customizing its use according to expression of BRCA1 and receptor-associated protein 80 (RAP80).9 One phase III randomized clinical trial was performed in European patients and an analogous phase II study was performed in China to address the important question of differential efficacy of chemotherapy related to ethnicity.9 In both trials, patients in the control arm received docetaxel and cisplatin, whereas in the experimental arm, patients with low RAP80 expression received gemcitabine and cisplatin, those with intermediate/high RAP80 expression and low/intermediate BRCA1 expression received docetaxel and cisplatin, and those with intermediate/high RAP80 expression and high BRCA1 expression received docetaxel alone.9 Accrual was closed prematurely due to the absence of clinical benefit in the experimental arms, but the BREC trials provide proof-of-concept that an inter national, non-industry, biomarker-directed trial is feasible, and provide the groundwork for future research to define predictive models of chemotherapy outcome. The preclinical2 and clinical studies5,6 published in 2014 demonstrate that single TKIs cause an imbalance in EGFR-mutant networks resulting in STAT3 activation, and emphasize the need for novel combination therapies to overcome potential mechanisms of resistance, as well as adequate imaging tools for evaluation of response to targeted therapies. The recent promising data with nintetanib8 supplement the
2 | ADVANCE ONLINE PUBLICATION
current armamentarium available to patients with advanced-stage NSCLC, but do not address the need for validated biomarkers to identify specific patient subgroups who have a higher probability of responding to such antiangiogenic drugs. The collaborative Chinese–European BREC trials9 exemplify the feasibility of global industry-independent academic initiatives, and the need for biomarkers to be included in prospective pharmacogenomic clinical trials. Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Campus Can Ruti, Carretera Canyet s/n, 08916 Badalona, Barcelona, Spain (R.R.). Fundación Molecular Oncology Research (MORe), Quirón Dexeus University Hospital, Sabino Arana 5‑19, 08028 Barcelona, Spain (N.K.). Correpondence to: R.R. [email protected] Acknowledgements Work in the laboratory of R.R. is partially supported by a grant from La Caixa Foundation. Competing interests The authors declare no competing interests. 1.
2.
3.
4.
5.
6.
7.
8.
9.
Rosell, R., Bivona, T. G. & Karachaliou, N. Genetics and biomarkers in personalisation of lung cancer treatment. Lancet 382, 720–731 (2013). Lee, H. J. et al. Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells. Cancer Cell 26, 207–221 (2014). Gao, S. P. et al. Mutations in the EGFR kinase domain mediate STAT3 activation via IL‑6 production in human lung adenocarcinomas. J. Clin. Invest. 117, 3846–3856 (2007). Fan, W. et al. MET-independent lung cancer cells evading EGFR kinase inhibitors are therapeutically susceptible to BH3 mimetic agents. Cancer Res. 71, 4494–4505 (2011). Hachemi, M. et al. [18F]FDG positron emission tomography within two weeks of starting erlotinib therapy can predict response in non‑small cell lung cancer patients. PLoS ONE 9, e87629 (2014). Seto, T. et al. Erlotinib alone or with bevacizumab as a first line therapy in patients with advanced non-squamous non-small cell lung cancer harbouring epidermal growth factor receptor mutations (JO25567): a randomised phase II study. Lancet Oncol. 15, 1236–1244 (2014). Li, R. et al. Niclosamide overcomes acquired resistance to erlotinib through suppression of STAT3 in non-small cell lung cancer. Mol. Cancer Ther. 12, 2200–2212 (2013). Reck, M. et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non‑small‑cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 15, 143–155 (2014). Moran, T. et al. Two biomarker-directed randomized trials in European and Chinese patients with non‑small‑cell lung cancer: the BRCA1-RAP80 Expression Customization (BREC) studies. Ann. Oncol. 25, 2147–2155 (2014).
www.nature.com/nrclinonc © 2014 Macmillan Publishers Limited. All rights reserved
to the IL‑6/JAK1/STAT3 axis, STAT3 is also activated downstream of FGFR through PI3K (Figure 1). Lee and co-workers2 cotreated PC-9 cells with erlotinib and the FGFR inhibitor PD 173074 and/or the JAK inhibitor ruxolitinib. Although inhibition with each agent partially blocked erlotinibinduced STAT3 phosphorylation, combining both inhibitors completely suppressed STAT3 induction. These findings were expanded to other oncogene-addicted cancer cells, revealing a common cancer protective feedback mechanism triggered by MEKpathway inhibition.2 These data show that only by blocking all STAT3 feedback pathway mechanisms using drug combinations can we start to circumvent therapeutic resistance. Also in 2014, Hachemi et al. 5 showed that 18F‑FDG-PET–CT could be a useful clinical tool for early evaluation of targeted therapies. This study highlighted the value of 18F‑FDG-PET–CT as a means to monitor response to targeted therapies that do not induce rapid tumour shrinkage.5 A decrease in maximum standardized uptake value (SUV) of at least 21.6% soon after starting therapy could discriminate progressive disease from nonprogressive disease in patients, and was correlated with improved progression-free survival (PFS) and overall survival.5 However, 18F‑FDG-PET–CT might not detect cells that escape adaptive changes in response to therapeutic pressure. The
Optimizing lung cancer treatment approaches Rafael Rosell and Niki Karachaliou
In 2014, developments in our understanding of escape signalling circuits implicated in resistance to targeted agents in patients with lung cancer have led to improvements in tackling such resistance. The potential role for PET in the management of erlotinib therapy, novel combination therapies and pharmacogenomic-driven individualization of platinum‑based chemotherapy represent other key advances. Rosell, R. & Karachaliou, N. Nat. Rev. Clin. Oncol. advance online publication 23 December 2014; doi:10.1038/nrclinonc.2014.225
Great strides have been made in lung cancer therapy, but a cure remains elusive for the vast majority of patients. The high death toll from lung cancer and unsatisfactory results of treatment have spurred us to improve our understanding of the molecular basis of this disease. EGFR mutations are among the most-common driver mutations, and tumours with these aberrations respond well to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib or erlotinib, although these responses are often transient owing to drug resistance.1 One mechanism of drug resist ance to EGFR therapy is the T790M gatekeeper mutation within EGFR. A second mechanism is activation of alternative receptor tyrosine kinases that maintain signal ling via key downstream pathways despite sustained inhibition of EGFR.1 In 2014, studies that unravel some of the genetic alterations have enhanced progress in the field. In particular, Lee et al.2 noted that erlotinib increased phosphorylation of STAT3 via feedback mechanisms involving IL-6 and FGF in almost all tested lung cancer cell lines that harboured EGFR mutations, but did not affect phosphorylated STAT3 in EGFR wildtype cells. Activated STAT3 regulates tumour growth, invasion, proliferation, angiogenesis, immune response, and metabolic reprogramming, and therefore its activation enables the tumour to survive pressure caused by targeted therapies. Thus, STAT3 activation following erlotinib treatment represents an undervalued and deleterious response, and a better understanding of this effect could help circumvent mechanisms of resistance to EGFR TKIs.
Previous studies had shown that constitutively activated mutant EGFRs promoted the production and release of IL‑6, which signals through the gp130 common cytokine receptor signalling subunit and the Janus kinases (JAKs), leading to STAT3 phosphorylation.3 Paradoxically, erlotinib had been shown to induce MET-independent activation of STAT3 signalling in EGFR-mutant lung cancer cells.4 To identify upstream activators of STAT3, Lee et al.2 performed global gene-expression analysis in four EGFRmutant cell lines and found that 243 genes were upregulated by erlotinib, and demon strated a direct connection between the FGFR2/3 and STAT3 pathways. In addition
TGF-β
EGF
EGFR del19 L858R P T790M PI3K
AKT
P
RAS
P
RAF
TGF-βR
IL-6
FGF
IL-6R
FGFR2/3 FRS2
EGFR TKIs
JAK1/2
STAT3
JAK1/2
P
MEK1/2
STAT3
PI3K P
STAT3
P
VEGF
Figure 1 | Imbalance in EGFR-mutant signalling networks caused by single-agent TKI therapy. EGFR Nature Reviews | and Clinical Oncology TKIs induce activation of STAT3 through autocrine upregulation of the IL‑6–IL‑6R FGF–FGFR2/3 pathways.2 Activation of the RAS/RAF/MEK/ERK pathway downstream of EGFR is prevented by EGFR TKIs, whereas STAT3 is paradoxically hyperactivated via the IL-6R/JAK1/2/STAT3 axis. TGF‑β can also induce IL‑6 axis activation. Expression of FGFR2/3 is markedly increased in response to EGFR TKIs and activates STAT3 through PI3K. These mechanisms probably underlie resistance to these agents, which could potentially be overcome through combination therapy.
NATURE REVIEWS | CLINICAL ONCOLOGY
ADVANCE ONLINE PUBLICATION | 1 © 2014 Macmillan Publishers Limited. All rights reserved
YEAR IN REVIEW Key advances ■■ EGFR-inhibitor treatment of EGFR-mutant NSCLC leads to STAT3 activity, promoting disease progression; EGFR inhibition combined with FGFR/PI3K plus JAK inhibition or direct STAT3 inhibition blocks this pathway2,7 ■■ The clinical benefit of EGFR inhibitors combined with VEGF-targeted therapies paves the way to use combination therapy to improve outcomes in patients with EGFR-mutant NSCLC6 ■■ Academic initiatives such as the cooperative Chinese–European BREC studies to overcome the limited efficacy of platinum-based chemotherapy in patients with advanced-stage NSCLC should be strongly supported9
authors comment that one limitation was the lack of an established SUV cut-off to discriminate patients with metabolic progression from nonmetabolic progression, as well as establishing a reliable SUV cut-off.5 The senescence-related ‘reverse Warburg’ cell state compensates for the weakness of both RECIST and FDG-PET for evaluation of response to new targeted therapies. Until we have a more-appropriate imaging tool to assess response to targeted therapies, early changes in 18F‑FDG uptake can predict PFS, survival and response in NSCLC patients within 2 weeks of erlotinib treatment.5 This year, Seto et al.6 published a phase II randomized study in patients with EGFR mutant NSCLC that examined the potential benefit of adding bevacizumab to erlotinib, compared with erlotinib alone. This study represents a novel therapeutic approach for optimizing treatment and might pave the way for combination therapy to improve outcomes in EGFR-mutant NSCLC. Important differences in PFS were observed in patients receiving combined treatment, with an almost twofold increase in duration of PFS from 9.7 months for erlotinib alone to 16 months for erlotinib plus bevacizumab (P = 0.0015), a new landmark in the treatment of this disease.6 Although the authors suggested that the benefit of bevacizumab could be related partly to its antiangiogenic effect in normalizing the tumour vasculature and potentially enhancing access of erlotinib to the tumour, it is plausible that inhibition of VEGF signalling by bevacizumab could also contribute to attenuating induction of STAT3 phosphorylation by erlotinib.7 Nintedanib is an oral angiokinase inhi bitor that simultaneously targets multiple proangiogenic pathways mediated by VEGFR1–3, FGFR1–3, and PDGFRα and
PDGFRβ. The results of the LUME-Lung 1 trial,8 in which patients with NSCLC were randomized to second-line docetaxel plus placebo or docetaxel plus nintetanib, provided further support for this approach. Nintedanib plus docetaxel significantly improved PFS in the total study population (median 3.4 months versus 2.7 months, P = 0.0019), and overall survival was prolonged in patients with adenocarcinoma (median 12.6 months versus 10.3 months, P = 0.0359).8 Despite lacking genomic profiling or biomarker assessments, this trial has contributed greatly to improving second-line therapy for advanced-stage NSCLC. Platinum-based chemotherapy remains the cornerstone of treatment for most patients with advanced-stage NSCLC and any effort to customize chemotherapy remains of great relevance. In a global academic collaborative effort without any industry funding, the BRCA1-RAP80 Expression Customization (BREC) studies investigated an approach to increase the efficacy of cisplatin by customizing its use according to expression of BRCA1 and receptor-associated protein 80 (RAP80).9 One phase III randomized clinical trial was performed in European patients and an analogous phase II study was performed in China to address the important question of differential efficacy of chemotherapy related to ethnicity.9 In both trials, patients in the control arm received docetaxel and cisplatin, whereas in the experimental arm, patients with low RAP80 expression received gemcitabine and cisplatin, those with intermediate/high RAP80 expression and low/intermediate BRCA1 expression received docetaxel and cisplatin, and those with intermediate/high RAP80 expression and high BRCA1 expression received docetaxel alone.9 Accrual was closed prematurely due to the absence of clinical benefit in the experimental arms, but the BREC trials provide proof-of-concept that an inter national, non-industry, biomarker-directed trial is feasible, and provide the groundwork for future research to define predictive models of chemotherapy outcome. The preclinical2 and clinical studies5,6 published in 2014 demonstrate that single TKIs cause an imbalance in EGFR-mutant networks resulting in STAT3 activation, and emphasize the need for novel combination therapies to overcome potential mechanisms of resistance, as well as adequate imaging tools for evaluation of response to targeted therapies. The recent promising data with nintetanib8 supplement the
2 | ADVANCE ONLINE PUBLICATION
current armamentarium available to patients with advanced-stage NSCLC, but do not address the need for validated biomarkers to identify specific patient subgroups who have a higher probability of responding to such antiangiogenic drugs. The collaborative Chinese–European BREC trials9 exemplify the feasibility of global industry-independent academic initiatives, and the need for biomarkers to be included in prospective pharmacogenomic clinical trials. Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Campus Can Ruti, Carretera Canyet s/n, 08916 Badalona, Barcelona, Spain (R.R.). Fundación Molecular Oncology Research (MORe), Quirón Dexeus University Hospital, Sabino Arana 5‑19, 08028 Barcelona, Spain (N.K.). Correpondence to: R.R. [email protected] Acknowledgements Work in the laboratory of R.R. is partially supported by a grant from La Caixa Foundation. Competing interests The authors declare no competing interests. 1.
2.
3.
4.
5.
6.
7.
8.
9.
Rosell, R., Bivona, T. G. & Karachaliou, N. Genetics and biomarkers in personalisation of lung cancer treatment. Lancet 382, 720–731 (2013). Lee, H. J. et al. Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells. Cancer Cell 26, 207–221 (2014). Gao, S. P. et al. Mutations in the EGFR kinase domain mediate STAT3 activation via IL‑6 production in human lung adenocarcinomas. J. Clin. Invest. 117, 3846–3856 (2007). Fan, W. et al. MET-independent lung cancer cells evading EGFR kinase inhibitors are therapeutically susceptible to BH3 mimetic agents. Cancer Res. 71, 4494–4505 (2011). Hachemi, M. et al. [18F]FDG positron emission tomography within two weeks of starting erlotinib therapy can predict response in non‑small cell lung cancer patients. PLoS ONE 9, e87629 (2014). Seto, T. et al. Erlotinib alone or with bevacizumab as a first line therapy in patients with advanced non-squamous non-small cell lung cancer harbouring epidermal growth factor receptor mutations (JO25567): a randomised phase II study. Lancet Oncol. 15, 1236–1244 (2014). Li, R. et al. Niclosamide overcomes acquired resistance to erlotinib through suppression of STAT3 in non-small cell lung cancer. Mol. Cancer Ther. 12, 2200–2212 (2013). Reck, M. et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non‑small‑cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 15, 143–155 (2014). Moran, T. et al. Two biomarker-directed randomized trials in European and Chinese patients with non‑small‑cell lung cancer: the BRCA1-RAP80 Expression Customization (BREC) studies. Ann. Oncol. 25, 2147–2155 (2014).
www.nature.com/nrclinonc © 2014 Macmillan Publishers Limited. All rights reserved
![[Lung cancer screening--update 2014].](/assets/img/hold.png)
