PARP and PARG inhibitors in cancer treatment

Abstract

Oxidative and replication stress underlie genomic instability of cancer cells. Amplifying genomic instability through radiotherapy and chemotherapy has been a powerful but nonselective means of killing cancer cells. Precision medicine has revolutionized cancer therapy by putting forth the concept of selective targeting of cancer cells. Poly(ADP-ribose) polymerase (PARP) inhibitors represent a successful example of precision medicine as the first drugs targeting DNA damage response to have entered the clinic. PARP inhibitors act through synthetic lethality with mutations in DNA repair genes and were approved for the treatment of BRCA mutated ovarian and breast cancer. PARP inhibitors destabilize replication forks through PARP DNA entrapment and induce cell death through replication stress-induced mitotic catastrophe. Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) exploit and exacerbate replication deficiencies of cancer cells and may complement PARP inhibitors in targeting a broad range of cancer types with different sources of genomic instability. Here I provide an overview of the molecular mechanisms and cellular consequences of PARP and PARG inhibition. I highlight clinical performance of four PARP inhibitors used in cancer therapy (olaparib, rucaparib, niraparib, and talazoparib) and discuss the predictive biomarkers of inhibitor sensitivity, mechanisms of resistance as well as the means of overcoming them through combination therapy.

DNA Damage/Repair Management in Cancers

“…The clinical use of PARP inhibitors might extend especially after recognizing the genetic targets that stimulate or mimic HR deficiencies using CRISPR/Cas9. A study demonstrated that TP53 induced glycolysis and apoptosis regulator (TIGAR) is developed in various types of cancers, and the overall survival in ovarian cancer was decreased when the expression of TIGAR was increased [61]. Therefore, in order to improve the sensitivity of cancer cells to olaparib, TIGAR was knocked down which has an impact on metabolic pathways and increased the cytotoxic effects of olaparib.…”

Poly(ADP-Ribose) Polymerase Inhibition in Acute Lung Injury. A Reemerging Concept

“…The nuclear concentration of PAR may also provide an “energetic role”: it may be metabolized to ATP, which, in turn, is used by DNA-repair enzymes ( 5 , 6 ). The translational consequence of these observations was the emergence of a novel therapeutic concept emerged in the field of oncology: via PARP inhibition, DNA repair may be suppressed and, thereby, cancer cell death may be therapeutically induced ( 4 , 7 , 8 ). Subsequent work has discovered that the cytotoxic anticancer effect of PARP inhibitors is most pronounced when the cancer cells have mutations in their HRR (homologous recombination DNA repair) system because, in such instances, the PARP1-dependent DNA-repair system becomes the “last man standing” in the process of DNA repair; elimination of this system, in turn, produces remarkable antitumor efficacy in such tumors ( 7 , 8 ).…”

“…The translational consequence of these observations was the emergence of a novel therapeutic concept emerged in the field of oncology: via PARP inhibition, DNA repair may be suppressed and, thereby, cancer cell death may be therapeutically induced ( 4 , 7 , 8 ). Subsequent work has discovered that the cytotoxic anticancer effect of PARP inhibitors is most pronounced when the cancer cells have mutations in their HRR (homologous recombination DNA repair) system because, in such instances, the PARP1-dependent DNA-repair system becomes the “last man standing” in the process of DNA repair; elimination of this system, in turn, produces remarkable antitumor efficacy in such tumors ( 7 , 8 ). Accordingly, ultrapotent (or third-generation) PARP inhibitors (such as olaparib, rucaparib, niraparib, and talazoparib) have recently been clinically approved in many countries); the approved therapeutic indications are typically HRR-deficient tumors (e.g., tumors with BRCA1 or BRCA2 mutations) ( 7 , 8 ).…”

The role of ADP-ribose metabolism in metabolic regulation, adipose tissue differentiation, and metabolism

“…There are pharmacological inhibitors available for the study of PARP biology, as well as for clinical use. Clinically available PARP inhibitors include ABT-888 (Veliparib from Abbott/Abbvie) rucaparib (Rubraca from Agouron/Pfizer/Clovis), talazoparib (Talzenna from Lead/Biomarin/Medivation/Pfizer), olaparib (Lynparza from KuDos Pharmaceuticals/Astra-Zeneca+Merck), and niraparib (Zejula from Merck/ Tesaro/GSK) (for detailed review, see Slade 2020;Curtin and Szabo 2013). Although, none of the current PARP inhibitors seem to discriminate between PARP enzymes (Wahlberg et al 2012), enzyme-specific inhibition of mono-PARP enzymes may be possible (Venkannagari et al 2016;Upton et al 2017;Holechek et al 2018).…”