Abstract
Editorial summaryInhibitors of poly(ADP-ribose) polymerase (PARPi) have entered the clinic for the treatment of patients with cancers that lack homology-directed DNA repair, but drug resistance remains a clinical hurdle. Recent advances in the identification of PARPi resistance mechanisms have yielded a better understanding of DNA end protection and the relevance of endogenous poly(ADP-ribose) glycohydrolase, highlighting new vulnerabilities.
Highlights
Inhibitors of poly(ADP-ribose) polymerase (PARPi) have entered the clinic for the treatment of patients with cancers that lack homology-directed DNA repair, but drug resistance remains a clinical hurdle
Hanzlikova et al [2] suggested that unligated Okazaki fragments resulting from PARP inhibitors (PARPi) are the responsible structures
Among the resistance mechanisms identified to date, restoration of homologydirected DNA repair is frequently observed in various model systems and in patients, highlighting the homologous recombination (HR) defect as the Achilles heel for PARPi
Summary
Inhibitors of poly(ADP-ribose) polymerase (PARPi) have entered the clinic for the treatment of patients with cancers that lack homology-directed DNA repair, but drug resistance remains a clinical hurdle. Among the resistance mechanisms identified to date, (partial) restoration of homologydirected DNA repair is frequently observed in various model systems and in patients, highlighting the HR defect as the Achilles heel for PARPi (reviewed in [1]). Loss of 53BP1 function facilitates BRCA1-independent end resection and conveys PARPi resistance.
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