Targeting the BRCA1 / 2 deficient cancer with PARP inhibitors: Clinical outcomes and mechanistic insights

BRCA1 and BRCA2 play a critical role in a variety of molecular processes related to DNA metabolism, including homologous recombination and mediating the replication stress response. Individuals with mutations in the and ( ) genes have a significantly higher risk of developing various types of cancers, especially cancers of the breast, ovary, pancreas, and prostate. Currently, the Food and Drug Administration (FDA) has approved four PARP inhibitors (PARPi) to treat cancers with mutations. In this review, we will first summarize the clinical outcomes of the four FDA-approved PARPi in treating deficient cancers. We will then discuss evidence supporting the hypothesis that the cytotoxic effect of PARPi is likely due to inducing excessive replication stress at the difficult-to-replicate (DTR) genomic regions in mutated tumors. Finally, we will discuss the ongoing preclinical and clinical studies on how to combine the PARPi with immuno-oncology drugs to further improve clinical outcomes.