The ALK tyrosine kinase inhibitor (TKI), crizotinib, shows significant activity in patients whose lung cancers harbor ALK fusions but its efficacy is limited by variable primary responses and acquired resistance. In work arising from the intriguing clinical observation of a patient with ALK fusion+ lung cancer who had an ‘exceptional response’ to an IGF-1R antibody, we define a therapeutic synergism between ALK and IGF-1R inhibitors. Similar to IGF-1R, ALK fusion proteins bind to the adaptor, IRS-1, and IRS-1 knockdown enhances the anti-tumor effects of ALK inhibitors. In models of ALK TKI resistance, the IGF-1R pathway is activated, and combined ALK/IGF-1R inhibition improves therapeutic efficacy. Consistent with this finding, IGF-1R/IRS-1 levels are increased in biopsy samples from patients progressing on crizotinib therapy. Collectively, these data support a role for the IGF-1R/IRS-1 pathway in both ALK TKI-sensitive and TKI-resistant states and provide biological rationale for further clinical development of dual ALK/IGF-1R inhibitors.

Purpose: MET is a potential therapeutic target in lung cancer and both MET tyrosine kinase inhibitors and monoclonal antibodies have entered clinical trials. MET signaling can be activated by various mechanisms, including gene amplification. In this study, we aimed to investigate MET amplification status in adenoand squamous cell carcinomas of the lung. We propose clearly defined amplification scores and provide epidemiologic data on MET amplification in lung cancer.Experimental Design: We evaluated the prevalence of increased MET gene copy numbers in 693 treatment-na€ ve cancers by FISH, defined clear cutoff criteria, and correlated FISH results to MET IHC.Results: Two thirds (67%) of lung cancers do not have gains in MET gene copy numbers, whereas 3% show a clear-cut high-level amplification (MET/centromer7 ratio !2.0 or average gene copy number per nucleus !6.0 or !10% of tumor cells containing !15 MET copies). The remaining cases can be subdivided into intermediate-(6%) and low-level gains (24%). Importantly, MET amplifications occur at equal frequencies in squamous and adenocarcinomas without or with EGFR or KRAS mutations.Conclusion: MET amplification is not a mutually exclusive genetic event in therapy-na€ ve non-small cell lung cancer. Our data suggest that it might be useful to determine MET amplification (i) before EGFR inhibitor treatment to identify possible primary resistance to anti-EGFR treatment, and (ii) to select cases that harbor KRAS mutations additionally to MET amplification and, thus, may not benefit from MET inhibition. Furthermore, our study provides comprehensive epidemiologic data for upcoming trials with various MET inhibitors. Clin Cancer Res; 21(4); 907-15. Ó2014 AACR.

The 8p12 locus (containing the FGFR1 tyrosine kinase gene) is frequently amplifi ed in squamous cell lung cancer. However, it is currently unknown which of the 8p12-amplifi ed tumors are also sensitive to fi broblast growth factor receptor (FGFR) inhibition. We found that, in contrast with other recurrent amplifi cations, the 8p12 region included multiple centers of amplifi cation, suggesting marked genomic heterogeneity. FGFR1 -amplifi ed tumor cells were dependent on FGFR ligands in vitro and in vivo . Furthermore, ectopic expression of FGFR1 was oncogenic, which was enhanced by expression of MYC. We found that MYC was coexpressed in 40% of FGFR1 -amplifi ed tumors. Tumor cells coexpressing MYC were more sensitive to FGFR inhibition, suggesting that patients with FGFR1-amplifi ed and MYC-overexpressing tumors may benefi t from FGFR inhibitor therapy. Thus, both cell-autonomous and non-cell-autonomous mechanisms of transformation modulate FGFR dependency in FGFR1 -amplifi ed lung cancer, which may have implications for patient selection for treatment with FGFR inhibitors. SIGNIFICANCE:Amplifi cation of FGFR1 is one of the most frequent candidate targets in lung cancer. Here, we show that multiple factors affect the tumorigenic potential of FGFR1 , thus providing clinical hypotheses for refi nement of patient selection. Cancer Discov; 4(2);