Molecular determinants of sensitivity to poly(ADP-ribose) polymerase inhibitors in epithelial ovarian cancer

Abstract

Less than half of patients with epithelial ovarian cancer (EOC) survive five years following diagnosis, underscoring the imperative need for improved treatment. Many patients, including those with advanced disease, initially respond to platinum agents, which constitute the backbone of therapy. However, tumors ultimately become resistant, rendering further treatment ineffective. Additionally, the poor tolerability of these agents warrants the exploration of more targeted treatments – one such strategy is exploiting synthetic lethal genetic relationships. Recent genomic sequencing efforts have revealed that as many of half of EOCs have homologous recombination (HR) alterations. HR is a critical pathway for the repair of platinum-induced ICLs, thus compromised HR is hypothesized to explain the initial response to chemotherapy in many patients. Accordingly, women whose tumors harbor mutations in the critical HR genes, BRCA1 or BRCA2 (BRCA1/2), demonstrate improved prognosis. BRCA1/2 mutations also confer exquisite sensitivity to inhibitors of the enzyme, poly(ADP-ribose) polymerase 1 (PARPis), hence loss of BRCA1/2 and PARP1 is synthetic lethal. A number of models have been proposed to explain this synthetic lethality, yet a consensus model that accounts for the diverse cellular roles of BRCA1/2 and PARP1 has yet to be established. Delineating the precise molecular underpinnings of PARPi action in BRCA1/2-deficient cells will aid clinicians in identifying the appropriate population of women with EOC likely to benefit from PARPi treatment and provide insight into resistance mechanisms that arise in these patients. Combining this approach with retrospective analysis of PARPi clinical trials will best define the proper indication for PARPi in EOC and other human cancers.