title: Inhibitor-sensitive FGFR2 and FGFR3 mutations in lung squamous cell carcinoma.
abstract: A comprehensive description of genomic alterations in lung squamous cell carcinoma (lung SCC) has recently been reported, enabling the identification of genomic events that contribute to the oncogenesis of this disease. In lung SCC, one of the most frequently altered receptor tyrosine kinase families is the fibroblast growth factor receptor (FGFR) family, with amplification or mutation observed in all four family members. Here, we describe the oncogenic nature of mutations observed in FGFR2 and FGFR3, each of which are observed in 3% of samples, for a mutation rate of 6% across both genes. Using cell culture and xenograft models, we show that several of these mutations drive cellular transformation. Transformation can be reversed by small-molecule FGFR inhibitors currently being developed for clinical use. We also show that mutations in the extracellular domains of FGFR2 lead to constitutive FGFR dimerization. In addition, we report a patient with an FGFR2-mutated oral SCC who responded to the multitargeted tyrosine kinase inhibitor pazopanib. These findings provide new insights into driving oncogenic events in a subset of lung squamous cancers, and recommend future clinical studies with FGFR inhibitors in patients with lung and head and neck SCC.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Rachel G
authors.initials: RG
authors.lastname: Liao
authors.forename: Joonil
authors.initials: J
authors.lastname: Jung
authors.forename: Jeremy
authors.initials: J
authors.lastname: Tchaicha
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Wilkerson
authors.forename: Andrey
authors.initials: A
authors.lastname: Sivachenko
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Beauchamp
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Pugh
authors.forename: Chandra Sekhar
authors.initials: CS
authors.lastname: Pedamallu
authors.forename: D Neil
authors.initials: DN
authors.lastname: Hayes
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.forename: Robert I
authors.initials: RI
authors.lastname: Haddad
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hammerman
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D019281:Dimerization; D006801:Humans; D007191:Indazoles; D007377:Interleukin-3 / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D041681:NIH 3T3 Cells; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics* / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D007191:Indazoles; D007377:Interleukin-3; D008024:Ligands; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; C496353:FGFR2 protein, human; C496365:FGFR3 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3