Abstract B24: Using KRAS synthetic lethality to design novel therapeutic approaches to cancer

Abstract

Abstract Background: KRAS is among the most commonly mutated human cancer genes, and is mutated in approximately 20% of human tumors. In colorectal cancer KRAS mutation is a predictor of anti-EGFR treatment resistance and different KRAS mutations can lead to different anti-EGFR treatment responses. Despite this, KRAS has proven difficult to target with small molecule inhibitors. Identifying synthetic lethal interactions that occur only in the context of tumor specific KRAS mutations represents one approach that could be used to target tumor cells. Material and methods: To identify KRAS synthetic lethal interactions we have generated functional profiles of constitutively activated KRAS mutant cancers, using an integrated approach that involves cell viability screening. We used a panel of isogenic tumor cell lines carrying different KRAS mutations (G12D, G12S, G12V and G13D) where we performed siRNA screens using a library targeting kinases and kinase-related and tumor suppressor genes. The validation of the siRNA hits was performed in a panel of non-isogenic colorectal and pancreatic cell lines to assess the generality of the effect. By determining the effect on cell viability of each siRNA in each cell model we were able to identify KRAS mutation specific effects. Results: By using high throughput functional viability profiling in KRAS mutant models we have been able to identify a series of genetic dependencies specific for tumor cells with oncogenic KRAS mutations. We have also some exciting preliminary results with small molecule inhibitors, which target some of the genes that we identified as being critical for the survival of KRAS mutant cancers. Conclusion: Using functional viability profiling of a series of KRAS isogenic cell lines we have now identified and confirmed several KRAS synthetically lethal candidate genes. Our subsequent work will focus on dissecting of the molecular mechanisms responsible for these KRAS mutant selective effects, and possible combinations with other drugs clinically available. Citation Format: Sara Costa-Cabral, Eliana Marinari, Marieke Aarts, Jenna L. Riffell, Christopher Torrence, Christopher L. Lord, Alan Ashworth. Using KRAS synthetic lethality to design novel therapeutic approaches to cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr B24.