Cordelia D. McGehee

Abstract Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) induce regressions and extend progression-free survival (PFS) in ovarian cancer, especially in tumors with BRCA1 or BRCA2 mutations that impair homologous recombination repair. While recent studies have clarified the key roles of BRCA1, BRCA2, and PARP1 in replication fork stability, the downstream mechanisms that mediate PARPi-induced cytotoxicity and resistance remain incompletely understood.

Despite ongoing advances in therapeutics, cancer remains a significant cause of morbidity and mortality worldwide. This persistence is due to both limited efficacy of available treatments for advanced cancers and therapy-related toxicities that restrict their use. The balance between an effective cancer therapeutic and its negative side effects is a central problem in drug development and translational research.

Abstract Chemotherapy resistance in cancer remains a barrier to curative therapy in advanced disease. Dosing of chemotherapy is often chosen based on the maximum tolerated dosing principle; drugs that are more toxic to normal tissue are typically given in on-off cycles, whereas those with little toxicity are dosed daily.