Recent Advances in Enhancing the Therapeutic Index of PARP Inhibitors in Breast Cancer

Simple Summary Two to three percent of breast cancer patients harbor germline mutation of either BRCA1 or BRCA2 genes. Their tumor cells are deficient in homologous recombination, a BRCA-dependent DNA repair machinery. These deficient cells survive thanks to the PARP-mediated alternative pathway. Therefore, PARP inhibitors have already shown some level of efficiency in the treatment of metastatic breast cancer patients. Unfortunately, some tumor cells inevitably resist PARP inhibitors by different mechanisms. In this review, we (i) present the notion of homologous recombination deficiency and its evaluation methods, (ii) detail the PARP inhibitor clinical trials in breast cancer, (iii) briefly describe the mechanisms to PARP inhibitors resistance, and (iv) discuss some strategies currently under evaluation to enhance the therapeutic index of PARP inhibitors in breast cancer. As poly-(ADP)-ribose polymerase (PARP) inhibition is synthetic lethal with the deficiency of DNA double-strand (DSB) break repair by homologous recombination (HR), PARP inhibitors (PARPi) are currently used to treat breast cancers with mutated BRCA1/2 HR factors. Unfortunately, the increasingly high rate of PARPi resistance in clinical practice has dented initial hopes. Multiple resistance mechanisms and acquired vulnerabilities revealed in vitro might explain this setback. We describe the mechanisms and vulnerabilities involved, including newly identified modes of regulation of DSB repair that are now being tested in large cohorts of patients and discuss how they could lead to novel treatment strategies to improve the therapeutic index of PARPi.