Restored replication fork stabilization, a mechanism of PARP inhibitor resistance, can be overcome by cell cycle checkpoint inhibition

Abstract

Poly(ADP-ribose) polymerase (PARP) inhibition serves as a potent therapeutic option eliciting synthetic lethality in cancers harboring homologous recombination (HR) repair defects, such as BRCA mutations. However, the development of resistance to PARP inhibitors (PARPis) poses a clinical challenge. Restoration of HR competency is one of the many molecular factors contributing to PARPi resistance. Combination therapy with cell cycle checkpoint (ATR, CHK1, and WEE1) inhibitors is being investigated clinically in many cancers, particularly in ovarian cancer, to enhance the efficacy and circumvent resistance to PARPis. Ideally, inhibition of ATR, CHK1 and WEE1 proteins will abrogate G2 arrest and subsequent DNA repair via restored HR in PARPi-treated cells. Replication fork stabilization has recently been identified as a potential compensatory PARPi resistance mechanism, found in the absence of restored HR. ATR, CHK1, and WEE1 each possess different roles in replication fork stabilization, providing different mechanisms to consider when developing combination therapies to avoid continued development of drug resistance. This review examines the impact of ATR, CHK1, and WEE1 on replication fork stabilization. We also address the therapeutic potential for combining PARPis with cell cycle inhibitors and the possible consequence of combination therapies which do not adequately address both restored HR and replication fork stabilization as PARPi resistance mechanisms.