Overcoming PARP inhibitor resistance in ovarian cancer: what are the most promising strategies?

Abstract

Purpose: Ovarian cancer is the most lethal gynaecological malignancy. Despite the introduction of bevacizumab, standard chemotherapy has remained largely unchanged and the vast majority of patients will relapse within the first two years of diagnosis. However, results from recent clinical trials demonstrating clinical benefits of PARP inhibitor treatment are rapidly changing therapeutic options for many patients with ovarian cancer.

Methods: Given the introduction of new therapeutic options in the treatment of ovarian cancer, we critically review key clinical trials, areas of scientific research and its clinical relevance.

Results: Most notably, patients with BRCA1/2 mutant ovarian cancer benefit from maintenance treatment with PARP inhibitors after (complete or partial) response to platinum-based chemotherapy. Here, we discuss the mechanism of PARP inhibition, multiple drug resistance mechanisms, including BRCA reverse mutations, altered PARP expression, changes in DNA repair pathways, kinase activation and additional drug targets that may augment PARP inhibition.

Conclusion: Although the use of PARP inhibitors is a huge step forward, it is apparent that patients, both with and without BRCA-mutant ovarian cancer, will eventually become resistant to PARP inhibitors. Therefore, novel combination therapies may enhance PARP inhibitor efficacy and overcome resistance mechanisms.

Keywords: Clinical trials; Drug resistance; Drug targets; Ovarian cancer; PARP inhibitors.

Fig. 1

Resistance mechanisms and potential targets of combination therapies. A summary of resistance mechanisms and potential drug targets with a list of corresponding inhibitors that can be used in combination with PARPi