Understanding Resistance Mechanisms and Expanding the Therapeutic Utility of PARP Inhibitors

Abstract

Poly-(ADP-ribose) polymerase (PARP) inhibitors act through synthetic lethality in cells with defects in homologous recombination (HR) DNA repair caused by molecular aberrations such as BRCA mutations, and is approved for treatment in ovarian cancer, with promising clinical activity against other HR defective tumors including breast and prostate cancers. Three PARP inhibitors have been FDA approved, while another two have shown promising activity and are in late stage development. Nonetheless, both primary and secondary resistance to PARP inhibition have led to treatment failure, and the development of predictive biomarkers and the ability to identify and overcome mechanisms of resistance is vital for optimization of its clinical utility. Additionally, there has been evidence that PARP inhibition may have a therapeutic role beyond HR deficient tumors which warrants further investigation, both as single agent and in combination with other therapeutic modalities like cytotoxic chemotherapy, radiation, targeted therapy and immunotherapy. With new strategies to overcome resistance and expand its therapeutic utility, PARP inhibitors are likely to become a staple in our armamentarium of drugs in cancer therapeutics.

Keywords: PARP inhibitors; targeted therapy.

Figure 1

PARP inhibitors cause DNA DSB (double strand break) by via inhibition of PARP enzyme activity and PARP trapping. In HR (homologous recombination) competent tumors, tumor cells with intact homologous recombination repair will be able to survive. However, in BRCA1/2 mutant and other HR deficient cancers that are reliant on base-excision repair based on the PARP pathway, blockade of this pathway by PARP inhibition leads to synthetic lethality and cell death. Multiple resistance mechanisms against PARP inhibitors have been elucidated, including somatic mutations in p53BP1 (a); upregulation of drug efflux transporters such as PgP (b); and somatic mutations in BRCA gene leading to restoration of the open reading frame and thus BRCA function (c). Strategies to overcome resistance include intermittent dosing, combination strategies and drug modification to reduce drug efflux. Various combination strategies are currently underway to further exploit the role of PARP inhibitors, including combination with chemotherapy (i); radiation therapy (ii); targeted agents (iii) and immunotherapy (iv).