Abstract
The use of poly(ADP-ribose) polymerase inhibitor (PARPi) exploits synthetic lethality in solid tumors with homologous recombination repair (HRR) defects. Significant clinical benefit has been established in breast and ovarian cancers harboring BRCA1/2 mutations, as well as tumors harboring characteristics of "BRCAness."However, the durability of treatment responses is limited, and emerging data have demonstrated the clinical challenge of PARPi resistance. With the expanding use of PARPi, the significance of PARP therapy in patients pretreated with PARPi remains in need of significant further investigation. Molecular mechanisms contributing to this phenomenon include restoration of HRR function, replication fork stabilization, BRCA1/2 reversion mutations, and epigenetic changes. Current studies are evaluating the utility of combination therapies of PARPi with cell cycle checkpoint inhibitors, antiangiogenic agents, phosphatidylinositol 3-kinase/AKT pathway inhibitors, MEK inhibitors, and epigenetic modifiers to overcome this resistance. In this review, we address the mechanisms of PARPi resistance supported by preclinical models, examine current clinical trials applying combination therapy to overcome PARPi resistance, and discuss future directions to enhance the clinical efficacy of PARPi.
Original language | English (US) |
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Pages (from-to) | 491-500 |
Number of pages | 10 |
Journal | Cancer Journal (United States) |
Volume | 27 |
Issue number | 6 |
DOIs | |
State | Published - Dec 27 2021 |
Funding
Conflicts of Interest and Source of Funding: S.N.W. has clinical research funding from ArQule, AstraZeneca, Bayer, Clovis Oncology, Cotinga Pharmaceuticals, Novartis, Roche/Genentech, and Tesaro. S.N.W. receives consulting fees from AstraZeneca, Clovis Oncology, MediVation, Merck, Ovation, Pfizer, Takeda, and Tesaro. This work was also supported in part by the MD Anderson Cancer Center Support Grant from the National Cancer Institute of the National Institutes of Health (NIH/NCI P30 CA016672), Ovarian SPORE NIH 1P50CA217685-01, the GOG Foundation, and the T32 training grant (NIH/NCI CA101642). For the remaining authors, none were declared.
Keywords
- Homologous recombination
- PARPi
- PARPi combination therapy
- PARPi resistance
ASJC Scopus subject areas
- Oncology
- Cancer Research