'Where is my gap': mechanisms underpinning PARP inhibitor sensitivity in cancer.

The introduction of poly-ADP ribose polymerase (PARP) inhibitors (PARPi) has completely changed the treatment landscape of breast cancer susceptibility 1-2 (BRCA1-BRCA2)-mutant cancers and generated a new avenue of research in the fields of DNA damage response and cancer therapy. Despite this, primary and secondary resistances to PARPi have become a challenge in the clinic, and novel therapies are urgently needed to address this problem. After two decades of research, a unifying model explaining sensitivity of cancer cells to PARPi is still missing. Here, we review the current knowledge in the field and the increasing evidence pointing to a crucial role for replicative gaps in mediating sensitization to PARPi in BRCA-mutant and 'wild-type' cancer cells. Finally, we discuss the challenges to be addressed to further improve the utilization of PARPi and tackle the emergence of resistance in the clinical context.