AUTHOR=Ragupathi Ashwin , Singh Manrose , Perez Alexis M. , Zhang Dong 

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

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=11

YEAR=2023

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2023.1133472

DOI=10.3389/fcell.2023.1133472

ISSN=2296-634X

ABSTRACT=<p>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 <italic>BRCA1</italic> and <italic>BRCA2</italic> (<italic>BRCA1/2</italic>) 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 <italic>BRCA1/2</italic> mutations. In this review, we will first summarize the clinical outcomes of the four FDA-approved PARPi in treating <italic>BRCA1/2</italic> 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 <italic>BRCA1/2</italic> 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.</p>