PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance

Maddison Rose; Joshua T Burgess; Kenneth O'Byrne; Derek J Richard; Emma Bolderson

doi:10.3389/fcell.2020.564601

PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance

Front Cell Dev Biol. 2020 Sep 9:8:564601. doi: 10.3389/fcell.2020.564601. eCollection 2020.

Authors

Maddison Rose¹, Joshua T Burgess¹, Kenneth O'Byrne^{1

2}, Derek J Richard¹, Emma Bolderson¹

Affiliations

¹ Cancer & Ageing Research Program, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Translational Research Institute, Queensland University of Technology, Brisbane, QLD, Australia.
² Princess Alexandra Hospital, Brisbane, QLD, Australia.

Abstract

The Poly (ADP-ribose) polymerase (PARP) family has many essential functions in cellular processes, including the regulation of transcription, apoptosis and the DNA damage response. PARP1 possesses Poly (ADP-ribose) activity and when activated by DNA damage, adds branched PAR chains to facilitate the recruitment of other repair proteins to promote the repair of DNA single-strand breaks. PARP inhibitors (PARPi) were the first approved cancer drugs that specifically targeted the DNA damage response in BRCA1/2 mutated breast and ovarian cancers. Since then, there has been significant advances in our understanding of the mechanisms behind sensitization of tumors to PARP inhibitors and expansion of the use of PARPi to treat several other cancer types. Here, we review the recent advances in the proposed mechanisms of action of PARPi, biomarkers of the tumor response to PARPi, clinical advances in PARPi therapy, including the potential of combination therapies and mechanisms of tumor resistance.

Keywords: BRCA; DNA damage; DNA repair; PARP inhibitors; cancer; targeted therapy.

Publication types

Review