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BRCAness, DNA gaps, and gain and loss of PARP inhibitor–induced synthetic lethality.

Authors :
Xin Li
Lee Zou
Source :
Journal of Clinical Investigation. 7/15/2024, Vol. 134 Issue 14, p1-12. 12p.
Publication Year :
2024

Abstract

Mutations in the tumor-suppressor genes BRCA1 and BRCA2 resulting in BRCA1/2 deficiency are frequently identified in breast, ovarian, prostate, pancreatic, and other cancers. Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA1/2-deficient cancer cells by inducing synthetic lethality, providing an effective biomarker-guided strategy for targeted cancer therapy. However, a substantial fraction of cancer patients carrying BRCA1/2 mutations do not respond to PARPis, and most patients develop resistance to PARPis over time, highlighting a major obstacle to PARPi therapy in the clinic. Recent studies have revealed that changes of specific functional defects of BRCA1/2-deficient cells, particularly their defects in suppressing and protecting single-stranded DNA gaps, contribute to the gain or loss of PARPi-induced synthetic lethality. These findings not only shed light on the mechanism of action of PARPis, but also lead to revised models that explain how PARPis selectively kill BRCA-deficient cancer cells. Furthermore, new mechanistic principles of PARPi sensitivity and resistance have emerged from these studies, generating potentially useful guidelines for predicting the PARPi response and design therapies for overcoming PARPi resistance. In this Review, we will discuss these recent studies and put them in context with the classic views of PARPi-induced synthetic lethality, aiming to stimulate the development of new therapeutic strategies to overcome PARPi resistance and improve PARPi therapy. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00219738
Volume :
134
Issue :
14
Database :
Academic Search Index
Journal :
Journal of Clinical Investigation
Publication Type :
Academic Journal
Accession number :
178485695
Full Text :
https://doi.org/10.1172/JCI181062