Frequent and Focal FGFR1 Amplification Associates with Therapeutically Tractable FGFR1 Dependency in Squamous Cell Lung Cancer
Jonathan Weiss,Martin L. Sos,Danila Seidel,Martin Peifer,Thomas Zander,Johannes M. Heuckmann,Roland T. Ullrich,Roopika Menon,Sebastian Maier,Alex Soltermann,Holger Moch,Patrick Wagener,Florian Fischer,Stefanie Heynck,Mirjam Koker,Jakob Schöttle,Frauke Leenders,Franziska Gabler,Ines Dabow,Silvia Querings,Lukas C. Heukamp,Hyatt Balke-Want,Sascha Ansén,Daniel Rauh,Ingelore Baessmann,Janine Altmüller,Zoe Wainer,Matthew Conron,Gavin M. Wright,Prudence A. Russell,Ben Solomon,Elisabeth Brambilla,Christian Brambilla,Philippe Lorimier,Steinar Sollberg,Odd Terje Brustugun,Walburga Engel-Riedel,Corinna Ludwig,Iver Petersen,Jörg Sänger,Joachim H. Clement,Harry J.M. Groen,Wim Timens,Hannie Sietsma,Erik Thunnissen,Egbert F. Smit,Daniëlle A.M. Heideman,Federico Cappuzzo,C. Ligorio,Stefania Damiani,Michael Hallek,Rameen Beroukhim,William Pao,Bert Klebl,Matthias Baumann,Reinhard Buettner,Karen Ernestus,Erich Stoelben,Jürgen Wolf,Peter Nürnberg,Peter Nürnberg,Sven Perner,Roman K. Thomas +62 more
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TLDR
F 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.Abstract:
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.read more
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Journal ArticleDOI
Comprehensive genomic characterization of squamous cell lung cancers
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