Is There a Role for Epigenetic Therapies in Modulating DNA Damage Repair Pathways to Enhance Chemotherapy and Overcome Drug Resistance?

SIMPLE SUMMARY: Epigenetic changes in a cell’s genome can cause the inactivation of genes and affect how tumours respond to chemotherapy. These epigenetic changes do not alter the DNA sequence and small molecule inhibitors of maintenance of the epigenetic state can change the sensitivity of a tumour to chemotherapy. Epigenetic therapies are being clinically evaluated as single agents or in combination with chemotherapies, including those that induce DNA damage. DNA damage induced by chemotherapy may be repaired and the cell either survives or alternatively cell death pathways are engaged and the cell is eliminated. Epigenetic silencing of gene expression during tumour development may lead to sensitivity of the tumour to chemotherapy if DNA repair of the DNA lesion is inactivated, or to chemotherapy resistance if cell death responses are inactivated. This illustrates the clinical challenge of using epigenetic therapies in combination with chemotherapy. Will such epigenetic drugs confer chemosensitivity and increased efficacy of chemotherapy, or induce resistance? Is there an effect of epigenetic therapies on normal cell chemo-sensitivity leading to increased toxicity? This review will illustrate the clinical challenges in combination studies of epigenetic therapies with chemotherapy and discuss future perspectives on addressing these challenges. ABSTRACT: Epigenetic therapies describe drug molecules such as DNA methyltransferase, histone methyltransferase and histone acetylase/deacetylase inhibitors, which target epigenetic mechanisms such as DNA methylation and histone modifications. Many DNA damage response (DDR) genes are epigenetically regulated in cancer leading to transcriptional silencing and the loss of DNA repair capacity. Epigenetic marks at DDR genes, such as DNA methylation at gene promoters, have the potential to be used as stratification biomarkers, identifying which patients may benefit from particular chemotherapy treatments. For genes such as MGMT and BRCA1, promoter DNA methylation is associated with chemosensitivity to alkylating agents and platinum coordination complexes, respectively, and they have use as biomarkers directing patient treatment options. In contrast to epigenetic change leading to chemosensitivity, DNA methylation of DDR genes involved in engaging cell death responses, such as MLH1, are associated with chemoresistance. This contrasting functional effect of epigenetic modification on chemosensitivity raises challenges in using DNA-demethylating agents, and other epigenetic approaches, to sensitise tumours to DNA-damaging chemotherapies and molecularly targeted agents. Demethylation of MGMT/BRCA1 could lead to drug resistance whereas demethylation of MLH1 could sensitise cells to chemotherapy. Patient selection based on a solid understanding of the disease pathway will be one means to tackle these challenges. The role of epigenetic modification of DDR genes during tumour development, such as causing a mutator phenotype, has different selective pressures and outcomes compared to epigenetic adaptation during treatment. The prevention of epigenetic adaptation during the acquisition of drug resistance will be a potential strategy to improve the treatment of patients using epigenetic therapies.