Perspectives on PARP inhibitors as pharmacotherapeutic strategies for breast cancer

Abstract

Introduction Approximately 10% of all breast cancer cases occur in individuals who have germline pathogenic variants of the BRCA 1, BRCA 2, and other genes associated with impaired DNA damage repair that is associated with an increased risk of breast, ovarian, and other cancers. Inhibitors of poly-ADP ribose polymerase (PARP) induce synthetic lethality in cancer cells harboring such pathogenic variants.Area covered In this review, the authors review the mechanisms of action, antitumor activity, and adverse events associated with PARP inhibitors for the treatment of advanced breast cancer. The authors then summarize the area and provide their expert perspectives on the area.Expert opinion Two PARP inhibitors are approved in metastatic breast cancer, including olaparib and talozaparib. Both agents were approved based on phase III trials demonstrating that they were associated with improved progression-free survival compared with treatment of physician's choice in patients receiving second-third line therapy for locally advanced, inoperable, or metastatic breast cancer in patients with germline pathogenic BRCA 1 or BRCA2 variants.

Keywords: BRCA 1 or 2 mutation; DNA repair defect; PARP inhibitor; breast cancer.

Figure 1

A) Structure of human PARP-1 Two zinc binding domains recognize particular DNA structures. The auto-modification domain contains a BRCT (BRCA1 C–terminus) fold. The catalytic domain composed of two subdomains, the helical subdomain (HD) and the ART subdomain, which includes the amino acids involved in catalysis and binding of NAD⁺ B). Mechanism of PARP PARP1 binds damaged DNA at SSBs and other DNA lesions which causes allosteric changes in the structure of PARP1 that activates catalytic function. Activated PARP1 PARylates and recruit DNA repair effector proteins. PARP1 eventually autoPARylates and the negative charge of PAR causes PARP1 release from repaired DNA. C)Synthetic lethality Single strand DNA break (SSB) is recognized by PARP and when PARP is blocked by PARP inhibitors SSB persists, results in double strand break (DSB). DSB is repaired via homologous recombination (HR) and BRCA 1 and 2 play major role. When BRCA is defective HR cannot occur which leads to error prone non-homologous end joining repair (NHEJ), increases genomic instability and eventually cell death. RF: replication fork, (Adapted from [127])

Figure 1

A) Structure of human PARP-1 Two zinc binding domains recognize particular DNA structures. The auto-modification domain contains a BRCT (BRCA1 C–terminus) fold. The catalytic domain composed of two subdomains, the helical subdomain (HD) and the ART subdomain, which includes the amino acids involved in catalysis and binding of NAD⁺ B). Mechanism of PARP PARP1 binds damaged DNA at SSBs and other DNA lesions which causes allosteric changes in the structure of PARP1 that activates catalytic function. Activated PARP1 PARylates and recruit DNA repair effector proteins. PARP1 eventually autoPARylates and the negative charge of PAR causes PARP1 release from repaired DNA. C)Synthetic lethality Single strand DNA break (SSB) is recognized by PARP and when PARP is blocked by PARP inhibitors SSB persists, results in double strand break (DSB). DSB is repaired via homologous recombination (HR) and BRCA 1 and 2 play major role. When BRCA is defective HR cannot occur which leads to error prone non-homologous end joining repair (NHEJ), increases genomic instability and eventually cell death. RF: replication fork, (Adapted from [127])

Figure 2.. PARP inhibitors that are in clinical use or in development

Chemical structure is obtained from FDA package insert of each PARP inhibitor. IC₅₀: half maximal inhibitory concentration, Ki: inhibition constants