Cancer treatment reviews
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Cancer treatment reviews · Dec 2018
ReviewRestored replication fork stabilization, a mechanism of PARP inhibitor resistance, can be overcome by cell cycle checkpoint inhibition.
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. ⋯ 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.