Abstract 5752: Molecular mechanisms driving oncogenesis in KRAS mutant non-small cell lung cancer

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC The poor prognosis associated with Non Small Cell Lung Cancers (NSCLC) harboring KRAS mutations (∼20-30% frequency) has highlighted the need for RAS targeted therapeutics in oncology for decades. However, attempts to target RAS directly using small molecule inhibitors have historically proven unsuccessful. Additionally, pre-clinical data repeatedly demonstrates that KRAS mutated cancer cells show variable responses to inhibition of downstream effectors, RAF, MEK and PI3K, suggesting that proliferation and survival may be driven through additional pathways and that the molecular mechanisms through which KRAS drives oncogenesis have yet to be fully elucidated. Moreover, parallel pathways activated in human lung cancer that might cooperate with RAS to maintain a transformed state, likewise remain poorly defined. By screening a panel of KRAS mutant NSCLCs for functional dependence on KRAS by shRNA knockdown, we have identified cell lines that require KRAS for proliferation and suppression of apoptosis. In an effort to identify the signaling pathways that promote cellular proliferation and survival in KRAS-mutant lung cancers we have conducted an unbiased cellular screen to identify shRNAs that mitigate dependence on the KRAS oncoprotein. Using this method we have identified molecular pathways that appear to cooperate with the KRAS oncogene to promote tumorogenesis and contribute to the distinct proliferative and apoptotic phenotypes of KRAS dependent NSCLC cell lines. 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 5752.