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

Ashwin Ragupathi; Manrose Singh; Alexis M Perez; Dong Zhang

doi:10.3389/fcell.2023.1133472

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

Front Cell Dev Biol. 2023 Mar 22:11:1133472. doi: 10.3389/fcell.2023.1133472. eCollection 2023.

Authors

Ashwin Ragupathi¹, Manrose Singh¹, Alexis M Perez¹, Dong Zhang¹

Affiliation

¹ Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY, United States.

Abstract

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

Keywords: BRCA1 and BRCA2; PARP inhibitors; PARP1; breast cancer; ovarian cancer; pancreatic cancer; prostate cancer; synthetic lethality.

Publication types

Review