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

Joshua T. Burgess,Kenneth O’Byrne,Derek J. Richard,Maddison Rose,Emma Bolderson

doi:10.3389/fcell.2020.564601

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.

Highlights

Cancer is a large subset of diseases characterized by the uncontrollable growth of abnormal cells
Women presenting with breast or ovarian tumors are routinely tested for hereditary mutations in BRCA1/2 and this guides whether they are treated with Poly (ADP-ribose) polymerase (PARP) inhibitors
A recent study showed that over 40% of BRCA1/2 mutations were somatic, suggesting that the tumors should be tested, to identify more patients that would benefit from PARP inhibitor treatment (Vos et al, 2020.) growing evidence suggests that BRCA1/2 mutational status does not always accurately correlate with PARP inhibitors (PARPi) sensitivity (Jonsson et al, 2019) and there is a need to find more accurate predictive PARPi biomarkers

Summary

INTRODUCTION

Cancer is a large subset of diseases characterized by the uncontrollable growth of abnormal cells. This auto-PARylation further activates PARP1 and enables the PARylation of histones and other chromatin-associated proteins (Chaudhuri and Nussenzweig, 2017) This auto- and hetero-modification recruits additional DNA repair molecules, such as XRCC1 to the site of damage, promoting the effective repair of DNA (Figure 1a) (Liu et al, 2017). PARP1, PARP2, and PARP3 share structural similarities and were shown to be activated in a similar manner through DNAdependent catalytic activation through a local destabilization of the catalytic domain (Langelier et al, 2014) Targeted therapies, such as PARPi, have greater specificity and less off-target side effects than traditional therapies, such as chemotherapy or radiation treatment, and can lead to more favorable outcomes in cancer patients. The two main pathways of DNA double strand break (DSB) repair are briefly described below

Homologous Recombination Repair

FDA EMA FDA EMA FDA

Metastatic pancreatic cancer

Relevant studies

PARPi BIOMARKERS

Homologous Recombination Deficiency Score

PROPOSED MECHANISMS OF ACTION OF PARP INHIBITORS

Inhibiting Single Strand Break Repair

Replication Fork Stalling and PARP Trapping

Disrupted Processing of Okazaki Fragments and Replication Fork Speed

PARPi RESISTANCE

Restoration of HR Activity