Mechanisms of Resistance to PARP Inhibitor and Its Combination Therapy Strategies to Improve Sensitivity in Ovarian Cancer

doi:10.12280/gjfckx.20230329

Abstract

Abstract:

Ovarian cancer is the most lethal gynecological malignancy. Poly (ADP-ribose) polymerase inhibitor (PARPi) impairs the repair of DNA single-stranded breaks through enzymatic inhibition and PARP "trapping". The synthetic lethal effect of PARPi in combination with tumor cells with a breast cancer-related gene (BRCA) deficiency or defective in homologous recombination repair (HRR) in ovarian cancer promoting its application in the maintenance therapy of ovarian cancer. However, resistance to PARPi is an obstacle to the long-term use of PARPi. A number of studies have described mechanisms of acquired resistance to PARPi, which include broadly HRR recovery, replication fork protection, reduced PARP "capture", and increased drug efflux. By targeting specific resistance mechanisms, the main combination therapeutic strategies currently being investigated include combining PARPi with anti-angiogenic agents, cell cycle checkpoint protein inhibitors, signalling pathway inhibitors, immunotherapy, epigenetic modifiers, etc. A combination therapy strategy of drugs has the potential to prevent and counteract PARPi resistance, thereby improving PARPi′s sensitivity and antitumor effects.

Key words: Poly(ADP-ribose) polymerase inhibitors, Ovarian neoplasms, Drug resistance, neoplasm, Drug therapy, combination

LI Bin, LIN Huan-huan, HAN Fei-fei, TIAN Mei-ling, DUAN Ai-hong, KE Xiao-ning. Mechanisms of Resistance to PARP Inhibitor and Its Combination Therapy Strategies to Improve Sensitivity in Ovarian Cancer[J]. Journal of International Obstetrics and Gynecology, 2023, 50(5): 563-567.

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