Increasing PARP inhibitor efficacy in ovarian cancer by targeting receptor tyrosine kinases

Introduction Ovarian cancer is the fifth most common gynaecological malignancies, with 8000 diagnoses in Germany per year. Since about 50 % of ovarian cancers demonstrate homologous recombination deficiency, the disease is most suitable for maintenance therapy with PARP inhibitors. Despite the promising result of several clinical trials, it is apparent that most if not all patients treated with PARP inhibitors will eventually become resistant.

Aim It has been shown that the receptor tyrosine kinase c-Met is implicated in PARP inhibitor resistance mechanisms in breast cancer models. Previous studies have shown that high c-Met expression correlates with a poor prognosis in ovarian cancer. We explore the pharmacological modulation of c-Met in conferring PARP inhibitor sensitivity in ovarian cancer.

Methods Molecular assays testing drug sensitivity in a variety of ovarian cancer cell lines.

Results We were able to show that neither selective c-Met inhibition nor siRNA-mediated knockdown increases PARP inhibitor sensitivity. We were able to show that a non-selective c-Met and VEGFR inhibitor (foretinib) may increase PARP inhibitor sensitivity in ovarian cancer cells, regardless of BRCA status.

Conclusion There is no clear evidence that selective c-Met inhibition or siRNA-mediated c-Met knockdown can increase PARP inhibitor sensitivity in the (5 tested) ovarian cancer cells. Since VEGFR-targeted therapy is already common clinical practice in treatment of ovarian cancer, the combination of foretinib and PARP inhibitors might warrant further investigation.

Publication History

Article published online:
07 October 2020