Journal
CANCER DISCOVERY
Volume 4, Issue 2, Pages 246-257Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-13-0323
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Funding
- German federal state North Rhine Westphalia (NRW)
- European Union as part of the PerMed NRW initiative [005-1111-0025]
- EU [HEALTH-F2-2010-258677]
- Deutsche Forschungsgemeinschaft [TH1386/3-1, SFB832, TP6, TP5]
- German Ministry of Science and Education (BMBF) as part of the NGFNplus program [01GS08100]
- Deutsche Krebshilfe as part of the Oncology Centers of Excellence
- Mildred-Scheel-Doktorandenprogramm [110770]
- Max Planck Society
- Behrens-Weise Foundation (M.I.F.A) [NEUR8061]
- Stand Up To Cancer Innovative Research Grant
- Program of the Entertainment Industry Foundation [SU2C-AACR-IR60109]
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The 8p12 locus (containing the FGFR1 tyrosine kinase gene) is frequently amplified in squamous cell lung cancer. However, it is currently unknown which of the 8p12-amplified tumors are also sensitive to fibroblast growth factor receptor (FGFR) inhibition. We found that, in contrast with other recurrent amplifications, the 8p12 region included multiple centers of amplification, suggesting marked genomic heterogeneity. FGFR1-amplified 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 amplified tumors. Tumor cells coexpressing MYC were more sensitive to FGFR inhibition, suggesting that patients with FGFR1-amplified and MYC-overexpressing tumors may benefit from FGFR inhibitor therapy. Thus, both cell-autonomous and non-cell-autonomous mechanisms of transformation modulate FGFR dependency in FGFR1-amplified lung cancer, which may have implications for patient selection for treatment with FGFR inhibitors. SIGNIFICANCE: Amplification 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 refinement of patient selection.
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