Triumphs and challenges in exploiting poly(ADP-ribose) polymerase inhibition to combat triple-negative breast cancer

Abstract

Poly(ADP‐ribose) polymerase 1 (PARP1) regulates a myriad of DNA repairmechanisms to preserve genomic integrity following DNA damage. PARP inhibitors(PARPi) confer synthetic lethality in malignancies with a deficiency in thehomologous recombination (HR) pathway. Patients with triple‐negative breastcancer (TNBC) fail to respond to most targeted therapies because their tumors lackexpression of the estrogen receptor, progesterone receptor, and human epidermalgrowth factor receptor 2. Certain patients with TNBC harbor mutations in HRmediators such as breast cancer susceptibility gene 1 (BRCA1) and breast cancersusceptibility gene 2 (BRCA2), enabling them to respond to PARPi. PARPi exploitsthe synthetic lethality of BRCA‐mutant cells. However, de novo and acquired PARPiresistance frequently ensue. In this review, we discuss the roles of PARP inmediating DNA repair processes in breast epithelial cells, mechanisms of PARPiresistance in TNBC, and recent advances in the development of agents designed toovercome PARPi resistance in TNBC.