Unlocking the Molecular Mechanisms of DNA Repair and Platinum Drug Resistance in Cancer Chemotherapy

This review article is devoted exclusively to DNA repair and acquired resistance to platinum compounds, with an emphasis on research needs and clinical application. It focuses on the role of genetic variants (gene mutations and SNPs) and epigenetic alterations (methylation and acetylation). Four major DNA repair pathways and one enzymecorrection mechanism are presented: Base Excision Repair, Nucleotide Excision Repair, DNA Double-Strand Break Repair, Mismatch Repair and Direct Damage Reversal. It is suggested that one cause of platinum resistance is more accurately described as alterations of DNA repair system rather than activation of DNA repair mechanism, as this cause of resistance is brought about by changes in genetic and epigenetic regulation. Given what is known, research on DNA repair and platinum resistance might best be directed at 1) transcriptional cis-elements (activators/repressors) within promoters of essential DNA repair genes, 2) effects of epigenetic alterations, and 3) connections between gene expression and DNA methylation or protein acetylation. Special attention should be directed at three interrelationships: between the different DNA repair pathways; between DNA methylation and protein acetylation; and between DNA repair pathways and DNA methylation or protein acetylation. Improved clinical outcomes may be achieved by restoring wild type p53 with small molecule drugs, the use of gene demethylation strategies, individual-targeted treatment of BRCA mutation carrier, and combining platinum compounds with molecularly-targeted drugs such as EGFR inhibitors.