Abstract 2426: Exacerbation of oxidative DNA damage as a synthetic lethal approach in mismatch repair deficient tumors

Abstract

Abstract The post-replicative DNA mismatch repair (MMR) pathway plays a key role in the maintenance of genomic stability. MMR corrects mismatches within the DNA helix that arise due to errors in nucleotide incorporation during either semi-conservative replication or synthesis associated with DNA repair. The importance of this system is testified by the fact that mutations affecting components of this repair pathway cause a “mutator” phenotype and predisposition to a wide variety of malignancies including colorectal, gastric, endometrial, and urothelial cancers. For example, the hereditable disorder Lynch syndrome (hereditary nonpolyposis colon cancer) is associated with germline loss of function mutations in the MMR tumor suppressor genes MLH1, MSH2, PMS2, and MSH6. In addition to this familial syndrome, MMR deficiency is present in 15% to 17% of all colorectal cancer cases. Synthetic lethal relationships have been identified that involve specific MMR genes, suggesting that synthetic lethal treatments could be applied to MMR deficient tumors. Previously, efforts to functionally identify genetic DNA mismatch repair synthetic lethalities and potential therapeutic targets have focused on the analysis of either candidate genes or relatively small gene subsets such as protein kinases. In order to define additional SL targets in MMR-deficient genetic backgrounds, we describe here the application of an shRNA screen in matched isogenic dMMR/pMMR (MMR-deficient/MMR-proficient) model cell lines. Using this screening approach, we identify new synthetic lethal interactions between MMR deficiency and components of the base excision repair and of the nucleotide sanitization systems, which restrict the extent of oxidative DNA damage. We propose that inhibition of the processes that minimize the oxidized DNA load could constitute a promising therapeutic approach in mismatch repair deficient cancers. Citation Format: Yari Fontebasso, Madeleine Hewish, Chris J. Lord, Alan Ashworth. Exacerbation of oxidative DNA damage as a synthetic lethal approach in mismatch repair deficient tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2426. doi:10.1158/1538-7445.AM2014-2426