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Inhibitor-sensitive FGFR2 and FGFR3 mutations in lung squamous cell carcinoma.
- Source :
-
Cancer research [Cancer Res] 2013 Aug 15; Vol. 73 (16), pp. 5195-205. Date of Electronic Publication: 2013 Jun 20. - Publication Year :
- 2013
-
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.
- Subjects :
- Animals
Carcinogenesis drug effects
Carcinogenesis genetics
Carcinogenesis metabolism
Carcinoma, Non-Small-Cell Lung drug therapy
Carcinoma, Non-Small-Cell Lung metabolism
Carcinoma, Squamous Cell drug therapy
Carcinoma, Squamous Cell metabolism
Cell Transformation, Neoplastic drug effects
Cell Transformation, Neoplastic genetics
Dimerization
Humans
Indazoles
Interleukin-3 genetics
Interleukin-3 metabolism
Ligands
Lung Neoplasms drug therapy
Lung Neoplasms metabolism
Mice
Mice, Nude
NIH 3T3 Cells
Protein Kinase Inhibitors pharmacology
Pyrimidines pharmacology
Receptor, Fibroblast Growth Factor, Type 2 metabolism
Receptor, Fibroblast Growth Factor, Type 3 metabolism
Sulfonamides pharmacology
Carcinoma, Non-Small-Cell Lung genetics
Carcinoma, Squamous Cell genetics
Lung Neoplasms genetics
Mutation
Receptor, Fibroblast Growth Factor, Type 2 genetics
Receptor, Fibroblast Growth Factor, Type 3 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 73
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 23786770
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-12-3950