Abstract 4713: Targeting the mitochondria for the treatment of MLH1-deficient disease

The DNA Mismatch repair (MMR) pathway is responsible for the repair of base-base mismatches and insertion/deletion loops that arise during DNA replication. MMR deficiency is currently estimated to be present in 15-17% of colorectal cancer cases and 30% of endometrial cancers. MLH1 is one of the key proteins involved in the MMR pathway. MMR deficient tumours are often resistant to standard chemotherapies, therefore there is a critical need to identify new therapeutic strategies to treat MMR deficient disease. We have performed synthetic lethal compound and RNAi screens to identify potential therapeutic targets for the treatment of MLH1 deficient tumours. Strikingly, upon analysis, a number of the hit compounds have been shown to target mitochondrial function. Our previous work has shown that MLH1 can localize to the mitochondria and silencing of the mitochondrial genes, POLG and PINK1 are synthetically lethal with MLH1 deficiency. We demonstrate that MLH1 deficient tumours are synthetically lethal with mitochondrial targeted agents (Menadione, Parthenolide) which are known to induce reactive oxygen species and cause oxidative stress as one of their main mechanisms of action. Upon functional analysis we show that loss of MLH1 is associated with a reduction in Complex I activity, reduced basal oxygen consumption rate, reduced spare respiratory capacity and reactive mitochondrial biogenesis (upregulation of pgc1β), suggesting that mitochondrial function is deregulated upon loss of MLH1. Taken together, our results thus far suggest that targeting the mitochondria may be a potential therapeutic strategy for the treatment of MLH1 deficient disease. Citation Format: Sukaina Rashid, Gemma Bridge, Zhi Yao, Gyorgy Szabadkai, Sarah A. Martin. Targeting the mitochondria for the treatment of MLH1-deficient disease. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4713. doi:10.1158/1538-7445.AM2015-4713