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Cancer Res DOI:10.1158/0008-5472.CAN-12-3950

Inhibitor-sensitive FGFR2 and FGFR3 mutations in lung squamous cell carcinoma.

Publication TypeJournal Article
Year of Publication2013
AuthorsLiao, RG, Jung, J, Tchaicha, J, Wilkerson, MD, Sivachenko, A, Beauchamp, EM, Liu, Q, Pugh, TJ, Pedamallu, CSekhar, D Hayes, N, Gray, NS, Getz, G, Wong, K-K, Haddad, RI, Meyerson, M, Hammerman, PS
JournalCancer Res
Volume73
Issue16
Pages5195-205
Date Published2013 Aug 15
ISSN1538-7445
KeywordsAnimals, Carcinogenesis, Carcinoma, Non-Small-Cell Lung, Carcinoma, Squamous Cell, Cell Transformation, Neoplastic, Dimerization, Humans, Interleukin-3, Ligands, Lung Neoplasms, Mice, Mice, Nude, Mutation, NIH 3T3 Cells, Protein Kinase Inhibitors, Pyrimidines, Receptor, Fibroblast Growth Factor, Type 2, Receptor, Fibroblast Growth Factor, Type 3, Sulfonamides
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.

URLhttp://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=23786770
DOI10.1158/0008-5472.CAN-12-3950
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/23786770?dopt=Abstract

Alternate JournalCancer Res.
PubMed ID23786770
PubMed Central IDPMC3749739
Grant ListP50CA090578 / CA / NCI NIH HHS / United States
R01 CA122794 / CA / NCI NIH HHS / United States
K08 CA163677 / CA / NCI NIH HHS / United States
F32 CA142039 / CA / NCI NIH HHS / United States
1K08CA163677 / CA / NCI NIH HHS / United States
T32 CA009172 / CA / NCI NIH HHS / United States
P01 CA154303 / CA / NCI NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
R01 CA140594 / CA / NCI NIH HHS / United States
P50 CA090578 / CA / NCI NIH HHS / United States
F32CA142039 / CA / NCI NIH HHS / United States