PARP inhibitors: review of mechanisms of action and BRCA1/2 mutation targeting

Abstract

Poly(ADP-ribose) polymerases have shown true promise in early clinical studies due to reported activity in BRCA-associated cancers. PARP inhibitors may represent a potentially important new class of chemotherapeutic agents directed at targeting cancers with defective DNA-damage repair. In order to widen the prospective patient population that would benefit from PARP inhibitors, predictive biomarkers based on a clear understanding of the mechanism of action are required. In addition, a more sophisticated understanding of the toxicity profile is required if PARP inhibitors are to be employed in the curative, rather than the palliative, setting. PARP inhibitors have successfully moved into clinical practice in the past few years, with approval granted from the Food and Drug Administration (FDA) and European Medicines Agency (EMA) within the past two years. The United States FDA approval of olaparib applies to fourth-line treatment in germline BRCA-mutant ovarian cancer, and European EMA approval of olaparib for maintenance therapy in both germline and somatic BRCA-mutant platinum-sensitive ovarian cancer. This review covers the current understanding of PARP, its inhibition, and the basis of the excitement surrounding these new agents. It also evaluates future approaches and directions required to achieve full understanding of the intricate interplay of these agents at the cellular level.

Emissive Synthetic Cofactors: A Highly Responsive NAD+Analogue Reveals Biomolecular Recognition Features

“…To restore cellular NAD + levels and thus counteract detrimental pathways, inhibition of NAD + ‐consuming enzymes, most notably poly(ADP‐ribose)polymerase 1 (PARP1) and CD38/CD157, has shown promise . The significance of NAD + ‐mediated processes necessitates the development of new tools and probes to facilitate biophysical analyses and the fabrication of effective discovery assays.…”

Biguanides in combination with olaparib limits tumorigenesis of drug‐resistant ovarian cancer cells through inhibition of Snail

“…Poly ADP ribose polymerase inhibitors (PARPi) are presently approved as maintenance therapy following platinum and taxol chemotherapy. PARPi function by blocking PARP1 protein, inducing synthetic lethality in HGSOC containing mutations in genes involved in the homologous recombination pathway of DNA repair (HR) . Olaparib was the first PARPi to be introduced as a maintenance treatment for ovarian cancer patients …”

DNA Mismatch Repair in Advanced Metastatic Prostate Carcinoma: Clinical Perspective

“…And it is also suggested that defective HR secondary to BRCA1 and BRCA2 mutations may render cancer cells particularly sensitive to inhibition of singles stranded binding proteins (SSB) repair through inhibition of PARP [17]. Particularly, PARP inhibitors such as olaparib and niraparib exhibited significant antitumor efficacy in ovarian, breast, and PCa with dysfunctional HR [18]. Moreover, these are being extensively investigated in multiple clinical trials.…”