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.

The dual-acting chemotherapeutic agent Alchemix induces cell death independently of ATM and p53

“…However, depletion of MSH2, critical to the MMR machinery, exacerbated rather than reduced the ALX-induced cellular DDR, demonstrating that the MMR pathway is dispensable for ALX-induced ATR activation (Fig.S7A). This suggests that tumour cells with deficiencies in MMR could be hypersensitive to the killing effects of ALX as previously observed for other structurally related anthraquinone-based agents 20,21 .…”

Aberrant Methylation of Different DNA Repair Genes Demonstrates Distinct Prognostic Value for Esophageal Cancer

“…However, the methylation of hMLH1 and hMSH2 had a large impact on the prognosis of patients because abnormal methylation of the MMR gene led to mismatch repair deficiency, which induced drug resistance to alkylating agents in tumor cells, thereby, finally influencing the prognosis of the patients [48]. Other than MGMT, the MMR system is probably a major mechanism of drug resistance to alkylating agents [48,49]. The combined methylation analysis of both MGMT and MMR genes will help us to better anticipate the drug resistance to alkylating agents in ESCC patients.…”

Loss of hMSH2 gene expression correlates with improved survival in patients with sporadic colorectal cancer

“…A possible explanation of this phenomenon would be that high frequency of mutations characteristic of mismatch repairdeficient tumours actually restricts tumour growth. Since functional gene is necessary for the proper balance between proliferation and apoptosis in both normal and cancer cells, there are many literature data supporting hypothesis that cancer cells are more sensitive to genetoxic treatment than normal cells (Pors and Patterson 2005).…”