Abstract 5754: Identification of pharmacologically tractable genes that are associated with oncogenic K-Ras dependency in colorectal cancers

Abstract

Abstract Summary We have previously shown that KRAS mutant lung and pancreatic cancer cells can be classified into two broad groups based on their requirement or dependency for sustained K-Ras activity. By supervised gene expression analyses, we derived a gene expression signature associated with K-Ras dependency, components of which represent candidate therapeutic targets. We have applied this strategy to KRAS mutant colorectal cancers (CRCs), which are notoriously refractory to conventional and targeted therapeutics. Moreover, the KRAS gene is now routinely sequenced to identify CRC patients that harbor KRAS mutations. Thus, patients with KRAS mutation-positive CRCs are given little recourse in terms of treatment options. We have found that, like lung and pancreatic cancer cell lines, KRAS mutant can be classified into K-Ras dependent and K-Ras independent groups. However, whereas K-Ras dependency in KRAS mutant lung and pancreatic cancer cells is associated with a well differentiated epithelial-like phenotype, K-Ras dependent CRC cells do not exhibit such an association. As such K-Ras dependent CRC cells exhibit a distinct molecular profile compared to K-Ras dependent lung and pancreatic cancer cells. We have identified a number of distinct kinase genes whose expression is associated with K-Ras dependency specifically in CRCs. Depletion of these genes by RNAi results in selective cytotoxic effects in K-Ras dependent CRC cells, suggesting that these genes may serve as candidate therapeutic targets in a subset of KRAS mutant CRCs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5754.