Abstract A16: Discovery and functional characterization of essential pathways in KRAS mutant cancers

KRAS oncogenes are present in 30% of all human cancers and are required for tumor development and maintenance and although clearly important efforts to target KRAS mutant tumors remains a major challenge. Several systematic approaches have been made to target these RAS-dependent cancers through small molecule screening and genome-scale RNAi screens to identify KRAS Synthetic Lethal (SL) genes. We applied and network based approached to integrate published KRAS SL screen data to uncover protein networks enriched with KRAS SL genes. We are using these proteins networks to generate a KRAS genetic interaction map (E-MAP) using combinatorial RNAi to identify candidate drug combinations, which may be useful to treat KRAS mutant cancers. Our network analysis revealed a dozen protein networks enriched with KRAS SL genes. Our pilot RNAi screen revealed that KRAS mutant tumors are sensitive to PAPR inhibition. Furthermore our isogenic models reveal that KRAS mutant cells harbor active DNA repair pathways in the absence of DNA damaging agents and are likely suffering from replication stress. A combinatorial RNAi screen revealed a KRAS specific synthetic lethal interaction with PARP inhibitors and knock down of MEK-ERK pathway genes. Our results suggest that PARP inhibitions have some efficacy in treating KRAS mutant tumors undergoing replication stress single agents and potentially combined with inhibitors of MEK-ERK signaling. Future studies are underway to determine if PAPR inhibitors...
Source: Molecular Cancer Therapeutics - Category: Cancer & Oncology Authors: Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research