Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 2, Issue 62, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.3001451
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Funding
- Deutsche Krebshilfe [107954]
- German Ministry of Science and Education (BMBF) [01GS08100, 01GS08101]
- Max Planck Society [M.I.F.A.NEUR8061]
- Deutsche Forschungsgemeinschaft (DFG) through SFB [TP6, TP5]
- Ministry for Innovation, Science, Research and Technology of the State of Nordrhein-Westfalen (MIWT) [4000-12 09]
- International Association for the Study of Lung Cancer
- NIH National Cancer Institute
- Royal Australasian College of Surgeons
- Australasian Society of Cardiac and Thoracic Surgeons Foundation
- Peter MacCallum Foundation
- Sequenom
- Sanofi-Aventis
- Merck
- Roche
- Infinity
- Boehringer
- AstraZeneca
- ATLAS Biolabs
- Novartis
- Novartis Institutes for BioMedical Research
- Molecular MD
- BMS
- Symphony Evolution
- Eli Lilly
- Boehringer Ingelheim through the University Medical Center Groningen
- [2008]
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Lung cancer remains one of the leading causes of cancer-related death in developed countries. Although lung adenocarcinomas with EGFR mutations or EML4-ALK fusions respond to treatment by epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibition, respectively, squamous cell lung cancer currently lacks therapeutically exploitable genetic alterations. We conducted a systematic search in a set of 232 lung cancer specimens for genetic alterations that were therapeutically amenable and then performed high-resolution gene copy number analyses. We identified frequent and focal fibroblast growth factor receptor 1 (FGFR1) amplification in squamous cell lung cancer (n = 155), but not in other lung cancer subtypes, and, by fluorescence in situ hybridization, confirmed the presence of FGFR1 amplifications in an independent cohort of squamous cell lung cancer samples (22% of cases). Using cell-based screening with the FGFR inhibitor PD173074 in a large (n = 83) panel of lung cancer cell lines, we demonstrated that this compound inhibited growth and induced apoptosis specifically in those lung cancer cells carrying amplified FGFR1. We validated the FGFR1 dependence of FGFR1-amplified cell lines by FGFR1 knockdown and by ectopic expression of an FGFR1-resistant allele (FGFR1(V561M)), which rescued FGFR1-amplified cells from PD173074-mediated cytotoxicity. Finally, we showed that inhibition of FGFR1 with a small molecule led to significant tumor shrinkage in vivo. Thus, focal FGFR1 amplification is common in squamous cell lung cancer and associated with tumor growth and survival, suggesting that FGFR inhibitors may be a viable therapeutic option in this cohort of patients.
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