Abstract C152: Mechanisms of KRAS dependency in pancreatic ductal adenocarcinoma.

Abstract

Abstract Currently, pancreatic ductal adenocarcinoma (PDAC) has a dismal <5% survival rate two years after initial diagnosis. Despite significant advances in development of signal transduction targeted therapies for some cancers, erlotinib, an EGFR inhibitor, in combination with gemcitabine, is the only targeted drug approved for treatment of PDAC. The frequency of KRAS oncogene mutations in PDAC is greater than 90%, thus inhibition of K-Ras4B protein function may have a significant impact on PDAC tumorigenesis. In support of this hypothesis, several recent studies demonstrated that KRAS mutant cancer cell lines display a strong dependence or addiction to mutant K-Ras for survival. Surprisingly, K-Ras addiction was not attributed to either the Raf or phosphoinositide 3-kinase (PI3K) effector pathways, which are two of the best-characterized Ras signaling effectors. These results suggest that other pathways are key for mutant KRAS dependency. Elucidating the effector mechanism(s) necessary for KRAS addiction may implicate signaling pathways, which harbor novel therapeutic targets for future anti-K-Ras drug development. To address this question, we first verified that shRNA silencing of mutant KRAS in a panel of pancreatic cell lines led to a strong reduction in anchorage-independent growth. Notably and in contrast to published studies, this was not due to decreased cell survival or increased anoikis. Using KRAS mutant PDAC cell lines, we purpose to use effector domain mutants of oncogenic K-Ras4B that are differentially impaired in effector interaction and constitutively activated effectors to define the key effector(s) involved in KRAS dependency. These studies will help to define key signaling activities of mutant KRAS that are critical for oncogenesis in PDAC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C152.