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

Cancer Res
Authors
Keywords
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.

Year of Publication
2013
Journal
Cancer Res
Volume
73
Issue
16
Pages
5195-205
Date Published
2013 Aug 15
ISSN
1538-7445
URL
DOI
10.1158/0008-5472.CAN-12-3950
PubMed ID
23786770
PubMed Central ID
PMC3749739
Links
Grant list
P50CA090578 / 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