An update on PARP inhibitors—moving to the adjuvant setting

Abstract

Inhibition of poly(ADP-ribose) polymerase (PARP) enzymes is a potential synthetic lethal therapeutic strategy in cancers harbouring specific DNA-repair defects, including those arising in carriers of BRCA1 or BRCA2 mutations. Since the development of first-generation PARP inhibitors more than a decade ago, numerous clinical trials have been performed to validate their safety and efficacy, bringing us to the stage at which adjuvant therapy with PARP inhibitors is now being considered as a viable treatment option for patients with breast cancer. Nevertheless, the available data do not provide clear proof that these drugs are efficacious in the setting of metastatic disease. Advancement of a therapy to the neoadjuvant and adjuvant settings without such evidence is exceptional, but seems reasonable in the case of PARP inhibitors because the target population that might benefit from this class of drugs is small and well defined. This Review describes the evolution of PARP inhibitors from bench to bedside, and provides an up-to-date description of the key published or otherwise reported clinical trials of these agents. The specific considerations and challenges that might be encountered when implementing these compounds in the adjuvant treatment of breast cancer in the clinic are also highlighted.

BRCA1 recruitment to damaged DNA sites is dependent on CDK9

“…9 In cycling cells, if not repaired, SSBs tend to progress to DSBs that would be preferentially repaired through HR. 40,41 Consistent with our findings, CDK9-silenced cells exhibited an increased sensitivity to IR treatment that was intensified in the presence of a PARP inhibitor (Fig. 5).…”

PARP Inhibitors Sensitize Ewing Sarcoma Cells to Temozolomide-Induced Apoptosis via the Mitochondrial Pathway

“…To investigate the question whether PARP inhibitors modulate chemosensitivity of Ewing sarcoma cells, we screened the efficacy of several anticancer drugs that are used in the clinic for the treatment of Ewing sarcoma (11) in the presence and absence of PARP inhibitors. We used suboptimal drug concentrations of PARP inhibitors and anticancer drugs that caused up to % 20% reduction of cell viability when used as single agents compared with untreated control (Supplementary Fig.…”

“…Indeed, Ewing sarcoma cells have been shown to be particularly sensitive to PARP inhibition (9,10). Several PARP inhibitors including talazoparib (BMN-673), niraparib (MK-4827), olaparib (AZD-2281), and veliparib (ABT-888) are currently under investigation (11).…”

Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer

“…These preclinical findings suggest that patients with BRCA1-associated MBC may show poor response to olaparib and illustrate the value of GEMM-ESC models of human cancer for evaluation of novel therapeutics. resistance | mouse model | breast cancer | BRCA1 | PARP P oly(ADP-ribose) polymerase (PARP) inhibition provides a promising therapeutic strategy for targeting homologous recombination (HR)-deficient tumors, such as breast cancer 1 (BRCA1)-mutated cancers (1). Indeed, clinical phase I and phase II trials have shown potent anticancer activity of small molecule inhibitors of PARP, such as olaparib, in patients with BRCA1-associated breast cancer (2,3).…”