title: Cell-autonomous and non-cell-autonomous mechanisms of transformation by amplified FGFR1 in lung cancer.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 1Department of Translational Genomics, University of Cologne; 2Max-Planck-Institute for Neurological Research; Institutes of 3Pathology and 4Virology, University of Cologne;5Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne; 6Blackfield AG, Cologne; 7Technical University Dortmund, Dortmund, Germany; 8Medical Oncology and 9Institute of Pathology, Cantonal Hospital, Luzern; 10Novartis Pharma AG, Basel, Switzerland; and 11Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, India.
authors.forename: Florian
authors.initials: F
authors.lastname: Malchers
authors.forename: Felix
authors.initials: F
authors.lastname: Dietlein
authors.forename: Jakob
authors.initials: J
authors.lastname: Schöttle
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
authors.forename: Lucia
authors.initials: L
authors.lastname: Nogova
authors.forename: Kerstin
authors.initials: K
authors.lastname: Albus
authors.forename: Lynnette
authors.initials: L
authors.lastname: Fernandez-Cuesta
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Heuckmann
authors.forename: Oliver
authors.initials: O
authors.lastname: Gautschi
authors.forename: Joachim
authors.initials: J
authors.lastname: Diebold
authors.forename: Dennis
authors.initials: D
authors.lastname: Plenker
authors.forename: Masyar
authors.initials: M
authors.lastname: Gardizi
authors.forename: Matthias
authors.initials: M
authors.lastname: Scheffler
authors.forename: Marc
authors.initials: M
authors.lastname: Bos
authors.forename: Danila
authors.initials: D
authors.lastname: Seidel
authors.forename: Frauke
authors.initials: F
authors.lastname: Leenders
authors.forename: André
authors.initials: A
authors.lastname: Richters
authors.forename: Martin
authors.initials: M
authors.lastname: Peifer
authors.forename: Alexandra
authors.initials: A
authors.lastname: Florin
authors.forename: Prathama S
authors.initials: PS
authors.lastname: Mainkar
authors.forename: Nagaraju
authors.initials: N
authors.lastname: Karre
authors.forename: Srivari
authors.initials: S
authors.lastname: Chandrasekhar
authors.forename: Julie
authors.initials: J
authors.lastname: George
authors.forename: Steffi
authors.initials: S
authors.lastname: Silling
authors.forename: Daniel
authors.initials: D
authors.lastname: Rauh
authors.forename: Thomas
authors.initials: T
authors.lastname: Zander
authors.forename: Roland T
authors.initials: RT
authors.lastname: Ullrich
authors.forename: H Christian
authors.initials: HC
authors.lastname: Reinhardt
authors.forename: Francois
authors.initials: F
authors.lastname: Ringeisen
authors.forename: Reinhard
authors.initials: R
authors.lastname: Büttner
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Heukamp
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wolf
authors.forename: Roman K
authors.initials: RK
authors.lastname: Thomas
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D002898:Chromosomes, Human, Pair 8; D004195:Disease Models, Animal; D005784:Gene Amplification; D015870:Gene Expression; D020869:Gene Expression Profiling; D016259:Genes, myc; D018740:Genetic Heterogeneity; D064593:Heterografts; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D051379:Mice; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016896:Treatment Outcome
chemical_list: D008024:Ligands; D051496:Receptor, Fibroblast Growth Factor, Type 1