Squamous cell lung carcinoma (lung SCC) is the second most common subtype of non-small cell lung cancer with, 40,000 new cases diagnosed every year in the United States. Unlike lung adenocarcinoma, few targetable genomic events are known drivers of lung SCC, and therefore, therapeutic options are limited for patients with this disease. As part of The Cancer Genome Atlas (TCGA) project, we have analyzed the entire coding sequence of 196 lung SCCs for mutated genes which may be amenable to targeted therapeutics. In the 108 patient samples analyzed to date, we have observed mutations in the Fibroblast Growth Factor Receptor 3 (FGFR3) kinase gene in six cases at four sites, or 3% of samples. The observed FGFR3 mutations are present in both the extracellular domain and the kinase domain of the protein, an observation that is consistent with activating mutations in FGFR3 that are known to drive bladder cancer, and in fact, two of the observed mutations are at sites previously observed in bladder cancer. We therefore hypothesized that these mutations are oncogenic and may be driving transformation in a subset of lung SCC patients. Expression of mutated FGFR3 in NIH-3T3 cells led to anchorage-independent colony formation, which was inhibited by treatment with a pan-FGFR inhibitor. A known mechanism of FGFR3 activation is the constitutive dimerization of receptors with mutated extracellular domains via intermolecular disulfide bond formation, and we have observed this phenomenon in our ECD mutants as well. These data suggest that mutations in the FGFR3 gene are sufficient to transform cells. This finding, along with recently published data suggesting that FGFR1 amplification is also able to drive lung SCC development, demonstrates that the FGFR family may be a promising therapeutic target in lung SCC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2. doi:1538-7445.AM2012-2