title: Identification of Oncogenic and Drug-Sensitizing Mutations in the Extracellular Domain of FGFR2.
abstract: The discovery of oncogenic driver mutations and the subsequent developments in targeted therapies have led to improved outcomes for subsets of lung cancer patients. The identification of additional oncogenic and drug-sensitive alterations may similarly lead to new therapeutic approaches for lung cancer. We identify and characterize novel FGFR2 extracellular domain insertion mutations and demonstrate that they are both oncogenic and sensitive to inhibition by FGFR kinase inhibitors. We demonstrate that the mechanism of FGFR2 activation and subsequent transformation is mediated by ligand-independent dimerization and activation of FGFR2 kinase activity. Both FGFR2-mutant forms are predominantly located in the endoplasmic reticulum and Golgi but nevertheless can activate downstream signaling pathways through their interactions with fibroblast growth factor receptor substrate 2 (FRS2). Our findings provide a rationale for therapeutically targeting this unique subset of FGFR2-mutant cancers as well as insight into their oncogenic mechanisms.
authors.affiliation: Lowe Center for Thoracic Oncology, Boston, Massachusetts. Department of Medical Oncology, Boston, Massachusetts.
authors.forename: Junko
authors.initials: J
authors.lastname: Tanizaki
authors.affiliation: Lowe Center for Thoracic Oncology, Boston, Massachusetts. Department of Medical Oncology, Boston, Massachusetts.
authors.forename: Dalia
authors.initials: D
authors.lastname: Ercan
authors.affiliation: Lowe Center for Thoracic Oncology, Boston, Massachusetts. Department of Medical Oncology, Boston, Massachusetts.
authors.forename: Marzia
authors.initials: M
authors.lastname: Capelletti
authors.affiliation: Lowe Center for Thoracic Oncology, Boston, Massachusetts. Department of Medical Oncology, Boston, Massachusetts.
authors.forename: Michael
authors.initials: M
authors.lastname: Dodge
authors.affiliation: Lowe Center for Thoracic Oncology, Boston, Massachusetts. Department of Medical Oncology, Boston, Massachusetts.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Xu
authors.affiliation: Lowe Center for Thoracic Oncology, Boston, Massachusetts. Department of Medical Oncology, Boston, Massachusetts.
authors.forename: Magda
authors.initials: M
authors.lastname: Bahcall
authors.affiliation: Lowe Center for Thoracic Oncology, Boston, Massachusetts. Department of Medical Oncology, Boston, Massachusetts.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Tricker
authors.affiliation: Lowe Center for Thoracic Oncology, Boston, Massachusetts. Department of Medical Oncology, Boston, Massachusetts.
authors.forename: Mohit
authors.initials: M
authors.lastname: Butaney
authors.affiliation: Lowe Center for Thoracic Oncology, Boston, Massachusetts. Department of Medical Oncology, Boston, Massachusetts.
authors.forename: Antonio
authors.initials: A
authors.lastname: Calles
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Sholl
authors.affiliation: Department of Medical Oncology, Boston, Massachusetts. The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hammerman
authors.affiliation: Lowe Center for Thoracic Oncology, Boston, Massachusetts. Department of Medical Oncology, Boston, Massachusetts. Department of Medicine, Boston, Massachusetts.
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Oxnard
authors.affiliation: Lowe Center for Thoracic Oncology, Boston, Massachusetts. Department of Medical Oncology, Boston, Massachusetts. Department of Medicine, Boston, Massachusetts. Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.affiliation: Lowe Center for Thoracic Oncology, Boston, Massachusetts. Department of Medical Oncology, Boston, Massachusetts. Department of Medicine, Boston, Massachusetts. Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts. pasi_janne@dfci.harvard.edu.
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
mesh_terms: D000328:Adult; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006031:Glycosylation; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D041681:NIH 3T3 Cells; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D047428:Protein Kinase Inhibitors; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2