DNA Repair Inhibitors: Our Last Disposal to Improve Cancer Therapy

Modern cancer therapies, mainly ionizing radiation and certain classes of chemotherapies target DNA. Although these treatments disrupt the genome, their rationale is clear. They prevent cancer cells from dividing and proliferating. Nevertheless, cancer cells can survive by over-activating a wide range of DNA repair pathways to remove the induced damage. In this context, DNA repair is considered as a vital target to improve cancer therapy and reduce the resistance to many DNA damaging agent currently in use as standard of care treatments. Here, we focus on two important DNA repair pathways, namely base excision repair (BER) and nucleotide excision repair (NER). Specifically, our focus will be on two protein targets that are linked to the hallmark relapse or drug resistance phenomena. These are Excision Repair Cross-Complementation Group 1 (ERCC1), and DNA polymerase beta (pol β). The former is a key player in NER, while the latter is the error-prone polymerase of BER. Our objective is to list all known inhibitors for the two targets and provide an overview of the great efforts that were made for their discovery. While for the DNA pol β case, more than sixty inhibitors were identified, on the ERCC1 side, very few inhibitors have been discovered. It is hoped that the application of this review will assist in the discovery of novel, potent and specific drug candidates aimed at improving existing cancer therapies including ionizing radiation, bleomycin, monofunctional alkylating agents and cisplatin.