(ADP-Ribose) Polymerase Inhibition: “Targeted” Therapy

ancer Res ontrast to endocrine-sensitive and human epidermal growth factor receptor 2 (HER2)–positive breast , novel agents capable of treating advanced triple-negative breast cancer (TNBC) are lacking. Poly ribose) polymerase (PARP) inhibitors are emerging as one of the most promising “targeted” theras to treat TNBC, with the intended “target” being DNA repair. PARPs are a family of enzymes involved ltiple cellular processes, including DNA repair. TNBC shares multiple clinico-pathologic features with -mutated breast cancers, which harbor dysfunctional DNA repair mechanisms. Investigators hypoththat PARP inhibition, in conjunction with the loss of DNA repair via BRCA-dependent mechanisms, result in synthetic lethality and augmented cell death. This hypothesis has borne out in both prel models and in clinical trials testing PARP inhibitors in both BRCA-deficient and triple-negative cancer. The focus of this review includes an overview of the preclinical rationale for evaluating PARP tors in TNBC, the presumed mechanism of action of this novel therapeutic class, promising results everal influential clinical trials of PARP inhibition in advanced breast cancer (both TNBC and BRCA nt), proposed mechanisms of acquired resistance to PARP inhibitors, and, finally, concludes with deficie current challenges and future directions for the development of PARP inhibitors in the treatment of breast cancer. Clin Cancer Res; 16(19); 4702–10. ©2010 AACR.