Abstract 4423: Somatic mutations in the insulin-like growth factor-1 and insulin receptors found in cancer genomes result in constitutive activation of the receptor kinases

Abstract

Abstract Somatic mutations in receptor tyrosine kinases have been shown to be a mechanism by which tumor cells subvert signaling pathways to drive deregulated cell proliferation. The insulin-like growth factor 1 receptor (IGF-1R) and the related insulin receptor (InsR) regulate cell metabolism and cell proliferation by phosphorylating two related adapter proteins called insulin receptor substrates (IRS1/2). The IRS proteins are unique to the IGF-1R/InsR signaling pathway, and are recruited to the receptors by virtue of the interaction between the SH2 sequences of IRS1/2 and tyrosine auto-phosphorylation sites on the receptors. The complete sequence determination of cancer genomes has now made it possible to assess the extent of mutation in components of the IGF-1R/InsR signaling pathway. Analyses of The Cancer Genome Atlas (TCGA) data from colorectal cancer patients revealed that >25% of the tumor type have copy number gain in the genes encoding IRS2 or the ligand IGF2. These observations suggest a role for the IGF-1R/InsR signaling pathway in the pathobiology of colorectal cancer. To better understand the extent to which the IGF-1 and insulin receptors may be oncogenic drivers, we surveyed the TCGA data sets for somatic mutations in IGF-1R and InsR. To date, over 50 non-synonymous missense mutations in each of the two receptors have been identified across multiple tumor types. Mutations occur in both the extracellular and intracellular sequences, and few mutations are recurrent. cDNA containing IGF-1R and InsR mutations were analyzed for their intrinsic kinase activities. A number of mutations in the kinase domains resulted in constitutive activation of the receptor kinases, in a similar manner to what has been observed with other receptor tyrosine kinases. Effects of these mutations on the ability of the receptors to drive signal transduction and cell proliferation have been analyzed and will be reported. Results of these studies have further validated a role for the IGF-1R and InsR signaling pathway in cancer. Citation Format: Ann Greer, Stephen Hillerman, Han Chang, Tai Wai Wong. Somatic mutations in the insulin-like growth factor-1 and insulin receptors found in cancer genomes result in constitutive activation of the receptor kinases. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4423. doi:10.1158/1538-7445.AM2014-4423