Abstract 2931: Cancer cells deficient in DNA mismatch repair (MMR) are selectively sensitive to inhibition of the DNA dependent protein kinase (DNA-PK)

Many solid tumors, including a significant proportion of colorectal, endometrial, gastric and urothelial tract cancers, are functionally deficient in MMR. This results in an altered clinicopathological phenotype. With the objective of identifying potential MMR-deficient (dMMR) synthetic lethal vulnerabilities, we performed a large scale screen of drugs which included a library of kinase inhibitors. Using a pair of isogenic colorectal cancer (CRC) cell lines, deficient and proficient for MLH1, we identified that exposure to an inhibitor of the catalytic subunit of DNA-PK (Ku-57788) was associated with a reduction in cell viability in MLH1-deficient cells at nanomolar concentrations. Validation studies demonstrated a ten-fold difference in sensitivity in clonogenic assays and a significant correlation between MMR status and Ku-57788 across a panel of cancer cell lines. Inhibition of expression of DNA-PK using RNA interference reproduced the dMMR selectivity. The dMMR phenotype was associated with a reduction in cellular proliferation, leading to apoptosis. Given the role of MMR in the repair of oxidative damage, we assayed levels of 8-oxo-dG, a marker of oxidatively damaged DNA, and observed increased levels in dMMR cells. Upregulation of the anti-oxidant response was observed on exposure to Ku-57788, whilst addition of antioxidants to culture media resulted in complete abrogation of dMMR selectivity. We assessed the effect of combining Ku-57788 with standard chemotherapeutics used in CRC and observed a supra-additive effect with irinotecan. In vivo, treatment of CD1 nude mice with a DNA-PK inhibitor was associated with a reduction in growth of MLH1-deficient cancer cell line xenografts with no effect observed in MLH1-proficiency. We report for the first time that inhibition of DNA-PKcs using small molecule inhibitors, either as a single agent or in combination with chemotherapeutics, may be a potential therapeutic strategy for the treatment of cancers deficient in DNA MMR. Citation Format: Madeleine Hewish, Yari Fontebasso, Sarah A. Martin, Richard Elliott, Kerry L. Perks, Asha Konde, Ilirjana Bajrami, Antoinette Van Weverwijk, David Cunningham, Christopher J. Lord, Alan Ashworth. Cancer cells deficient in DNA mismatch repair (MMR) are selectively sensitive to inhibition of the DNA dependent protein kinase (DNA-PK). [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 2931. doi:10.1158/1538-7445.AM2014-2931