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

Frontiers in Cell and Developmental Biology

Cell and Developmental Biology

Ashwin Ragupathi¹  Alexis M. Perez¹  Manrose Singh¹  Dong Zhang² 

[1] Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY, United States;null;

关键词: BRCA1 and BRCA2;    PARP1;    PARP inhibitors;    synthetic lethality;    breast cancer;    ovarian cancer;    pancreatic cancer;    prostate cancer;   

DOI  :  10.3389/fcell.2023.1133472

 received in 2022-12-29, accepted in 2023-03-14,  发布年份 2023

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

Unknown   
Copyright © 2023 Ragupathi, Singh, Perez and Zhang.