Weiss, Jonathan, Sos, Martin L., Seidel, Danila, Peifer, Martin ORCID: 0000-0002-5243-5503, Zander, Thomas, Heuckmann, Johannes M., Ullrich, Roland T., Menon, Roopika, Maier, Sebastian, Soltermann, Alex, Moch, Holger, Wagener, Patrick, Fischer, Florian, Heynck, Stefanie, Koker, Mirjam, Schoettle, Jakob, Leenders, Frauke, Gabler, Franziska, Dabow, Ines, Querings, Silvia, Heukamp, Lukas C., Balke-Want, Hyatt, Ansen, Sascha, Rauh, Daniel ORCID: 0000-0002-1970-7642, Baessmann, Ingelore, Altmueller, Janine, Wainer, Zoe, Conron, Matthew, Wright, Gavin ORCID: 0000-0002-7000-9305, Russell, Prudence, Solomon, Ben, Brambilla, Elisabeth, Brambilla, Christian, Lorimier, Philippe, Sollberg, Steinar, Brustugun, Odd Terje, Engel-Riedel, Walburga, Ludwig, Corinna, Petersen, Iver, Saenger, Joerg, Clement, Joachim, Groen, Harry, Timens, Wim ORCID: 0000-0002-4146-6363, Sietsma, Hannie, Thunnissen, Erik ORCID: 0000-0001-5355-8508, Smit, Egbert, Heideman, Danielle, Cappuzzo, Federico, Ligorio, Claudia, Damiani, Stefania, Hallek, Michael, Beroukhim, Rameen, Pao, William, Klebl, Bert, Baumann, Matthias, Buettner, Reinhard, Ernestus, Karen, Stoelben, Erich, Wolf, Juergen, Nuernberg, Peter, Perner, Sven and Thomas, Roman K. (2010). Frequent and Focal FGFR1 Amplification Associates with Therapeutically Tractable FGFR1 Dependency in Squamous Cell Lung Cancer. Sci. Transl. Med., 2 (62). WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE. ISSN 1946-6242

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Weiss, JonathanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sos, Martin L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seidel, DanilaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, MartinUNSPECIFIEDorcid.org/0000-0002-5243-5503UNSPECIFIED
Zander, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heuckmann, Johannes M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ullrich, Roland T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Menon, RoopikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maier, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Soltermann, AlexUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moch, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wagener, PatrickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heynck, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koker, MirjamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schoettle, JakobUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leenders, FraukeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gabler, FranziskaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dabow, InesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Querings, SilviaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heukamp, Lukas C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Balke-Want, HyattUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ansen, SaschaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rauh, DanielUNSPECIFIEDorcid.org/0000-0002-1970-7642UNSPECIFIED
Baessmann, IngeloreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wainer, ZoeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Conron, MatthewUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wright, GavinUNSPECIFIEDorcid.org/0000-0002-7000-9305UNSPECIFIED
Russell, PrudenceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Solomon, BenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brambilla, ElisabethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brambilla, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lorimier, PhilippeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sollberg, SteinarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brustugun, Odd TerjeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Engel-Riedel, WalburgaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ludwig, CorinnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Petersen, IverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saenger, JoergUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clement, JoachimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Groen, HarryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Timens, WimUNSPECIFIEDorcid.org/0000-0002-4146-6363UNSPECIFIED
Sietsma, HannieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thunnissen, ErikUNSPECIFIEDorcid.org/0000-0001-5355-8508UNSPECIFIED
Smit, EgbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heideman, DanielleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cappuzzo, FedericoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ligorio, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Damiani, StefaniaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hallek, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beroukhim, RameenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pao, WilliamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klebl, BertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baumann, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ernestus, KarenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stoelben, ErichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perner, SvenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, Roman K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-490625
DOI: 10.1126/scitranslmed.3001451
Journal or Publication Title: Sci. Transl. Med.
Volume: 2
Number: 62
Date: 2010
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
Place of Publication: WASHINGTON
ISSN: 1946-6242
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
KINASE INHIBITORS; BREAST-CANCER; MUTATIONS; GEFITINIB; SENSITIVITY; CARCINOMAS; TUMOR; GENE; ADENOCARCINOMA; IDENTIFICATIONMultiple languages
Cell Biology; Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/49062

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