Malchers, Florian, Dietlein, Felix, Schottle, Jakob, Lu, Xin, Nogova, Lucia, Albus, Kerstin, Fernandez-Cuesta, Lynnette ORCID: 0000-0002-0724-6703, Heuckmann, Johannes M., Gautschi, Oliver, Diebold, Joachim, Plenker, Dennis, Gardizi, Masyar, Er, Matthias Scheffl, Bos, Marc, Seidel, Danila, Leenders, Frauke, Richters, Andre, Peifer, Martin ORCID: 0000-0002-5243-5503, Florin, Alexandra, Mainkar, Prathama S., Karre, Nagaraju, Chandrasekhar, Srivari, George, Julie, Silling, Steffi, Rauh, Daniel ORCID: 0000-0002-1970-7642, Zander, Thomas, Ullrich, Roland T., Reinhardt, H. Christian, Ringeisen, Francois, Buettner, Reinhard, Heukamp, Lukas C., Wolf, Juergen and Thomas, Roman K. (2014). Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Transformation by Amplified FGFR1 in Lung Cancer. Cancer Discov., 4 (2). S. 246 - 258. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 2159-8290

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Malchers, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dietlein, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schottle, JakobUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lu, XinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nogova, LuciaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Albus, KerstinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fernandez-Cuesta, LynnetteUNSPECIFIEDorcid.org/0000-0002-0724-6703UNSPECIFIED
Heuckmann, Johannes M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gautschi, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Diebold, JoachimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Plenker, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gardizi, MasyarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Er, Matthias SchefflUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bos, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seidel, DanilaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leenders, FraukeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Richters, AndreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, MartinUNSPECIFIEDorcid.org/0000-0002-5243-5503UNSPECIFIED
Florin, AlexandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mainkar, Prathama S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karre, NagarajuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chandrasekhar, SrivariUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
George, JulieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Silling, SteffiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rauh, DanielUNSPECIFIEDorcid.org/0000-0002-1970-7642UNSPECIFIED
Zander, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ullrich, Roland T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, H. ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ringeisen, FrancoisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heukamp, Lukas C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, Roman K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-447496
DOI: 10.1158/2159-8290.CD-13-0323
Journal or Publication Title: Cancer Discov.
Volume: 4
Number: 2
Page Range: S. 246 - 258
Date: 2014
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 2159-8290
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
FIBROBLAST GROWTH-FACTORS; THERAPEUTIC TARGET; COPY NUMBERS; MUTATIONS; SENSITIVITY; NVP-BGJ398; IDENTIFY; FAMILY; ROLESMultiple languages
OncologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/44749

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