Advances and perspectives of PARP inhibitors

Abstract

DNA damage repair deficiency leads to the increased risk of genome instability and oncogenic transformation. In the meanwhile, this deficiency could be exploited for cancer treatment by inducing excessive genome instability and catastrophic DNA damage. Continuous DNA replication in cancer cells leads to higher demand of DNA repair components. Due to the oncogenic loss of some DNA repair effectors (e.g. BRCA) and incomplete DNA repair repertoire, some cancer cells are addicted to certain DNA repair pathways such as Poly (ADP-ribose) polymerase (PARP)-related single-strand break repair pathway. The interaction between BRCA and PARP is a form of synthetic lethal effect which means the simultaneously functional loss of two genes lead to cell death, while defect in any single gene has a slight effect on cell viability. Based on synthetic lethal theory, Poly (ADP-ribose) polymerase inhibitor (PARPi) was developed aiming to selectively target cancer cells harboring BRCA1/2 mutations. Recently, a growing body of evidence indicated that a broader population of patients could benefit from PARPi therapy far beyond those with germline BRCA1/2 mutated tumors. Numerous biomarkers including homologous recombination deficiency and high level of replication pressure also herald high sensitivity to PARPi treatment. Besides, a series of studies indicated that PARPi-involved combination therapy such as PARPi with additional chemotherapy therapy, immune checkpoint inhibitor, as well as targeted agent had a great advantage in overcoming PARPi resistance and enhancing PARPi efficacy. In this review, we summarized the advances of PARPi in clinical application. Besides, we highlighted multiple promising PARPi-based combination strategies in preclinical and clinical studies.

Keywords: Combination therapy; DNA repair; Immune checkpoint inhibitor; PARPi; Synthetic lethal.

Fig. 1

PARP and PARPis. a The structure schematic of PARP molecule. There are six main domains of PARP1 which include three zinc finger-related domains (DNA binding domains), one BRCA1 C-terminus domain (auto-modification domain), one tryptophan-/glycine-/arginine-rich domain (WGR domain), and one catalytic domain. The catalytic domain of PARP1 consists of two subdomains: one helical domain (HD) and one ADP-ribosyltransferase catalytic domain (ART). b Three-dimensional structure of PARP1 molecule. The above structures were presented by PyMOL Molecular Graphics System (PDB ID: 5XST [104]). c The chemistry structural formula of PARPis. d The function of PARP and synthetic lethal interaction between PARP and HR. Once DNA SSB emerges, PARP1 could recognizes and interacts with SSB by its zinc finger-related domains. After PARP1 binding to damaged DNA chains, the auto-inhibitory function of HD is abrogated and the catalytic function of ART is activated. This catalytic activity leads to the generation of PAR chains on a series of target proteins which promotes the recruitment of DNA repair effectors and chromatin remodeling. Then the auto-PARylation on PARP1 protein causes the dissociation of PARP1 from DNA chains and restores the auto-inhibitory status of PARP1. For HR deficient tumor cells, active SSB repair pathways is the vital prerequisites for cell survival. After PARPi treatment, NHEJ is used to repair PARPi-introduced DSB. However, NHEJ is a rapid as well as error-prone repair pathway by direct ligation. Due to the low-fidelity, NHEJ often produces plenty of chromosomal rearrangements and these unsustainable DNA damages are harmful to cell viability