Clinical importance of DNA repair inhibitors in cancer therapy

Abstract

The efficacy of cancer chemotherapy and radiotherapy relies on generation of DNA damage. Since intrinsic DNA repair pathways enable cancer cells to survive by repairing these damaged lesions, inactivation of DNA repair coupled with chemotherapy and radiotherapy has a potential to enhance the effect of these therapies. Small molecule compounds that inhibit specific DNA repair proteins have been developed, and early clinical trials are ongoing. While DNA repair inhibitors have been tried mostly as a part of combination therapies with cytotoxic agents, recent reports highlighted a new concept in cancer therapy where DNA repair inhibitors could be used as single agents to selectively kill cancer cells. This concept is based on the findings that cancer cells are frequently defective in particular DNA repair pathway(s) and the presumption that inhibition of the compensatory repair pathway(s) in such cells might be useful to kill them. For example, poly(ADP-ribose) polymerase (PARP) plays a critical role in DNA base-excision repair, and inactivation of this protein increases the number of single-strand breaks, leading to double-strand breaks that require to be repaired by homologous recombination (HR) mediated by BRCA1 and BRCA2. Recently, BRCA1- or BRCA2-defective tumour cells were shown to be sensitive to PARP inhibitors alone. This treatment may be tumour-specific because only the BRCA1−/− or BRCA2−/− tumours in the BRCA1+/− or BRCA2+/− patients are completely defective in HR repair. The following short review aims at summarizing the basic mechanisms of DNA repair and the therapeutic options using DNA repair inhibitors in cancer therapy.