DNA mismatch repair deficiency, resistance to cancer chemotherapy and the development of hypersensitive agents

Abstract

DNA Mismatch Repair (MMR) deficiency results in resistance to platinating and alkylating agents, DNA minor groove binders, inhibitors of topoisomerases and antimetabolites. The cellular MMR pathway, involving hMLH1 and MSH2, detects and repairs DNA frame shifts replication errors and regulates recombination events. Tumour cells are able to cope with DNA damage caused by chemotherapy as long as the MMR-process is disabled and hence there is a need to develop agents that (i) restore MMR proficiency or (ii) are hypersensitive in cells that are irreversibly MMR deficient. Decitabine is suggested to restore MMR function by reversal of gene promoter hypermethylation of hMLH1. However, when MMR is deficient due to gene mutation it is not feasible to design agents, since the absence of functional proteins that constitute the MMR machinery are not available as targets. The evidence that resistance to chemotherapy is associated with hMSH2 and/or hMLH1 deficiency has revealed a new paradigm for drug discovery of agents that positively exploit this phenotype to therapeutic advantage. Even more attractive is the development of agents that are hypersensitive in the absence of functional MMR to enable even more effective treatment. In this regard, established agents such as mitomycin C, camptothecin or novel hydroxyethylaminoanthraquinones may represent opportunities for exploitation of MMR-deficiency in tumour cells.