Olaparib and Enzalutamide synergistically suppress HCC progression via the AR-mediated miR-146a-5p/BRCA1 signaling

Abstract

Hepatocellular carcinoma (HCC) is one of most common malignant tumors worldwide, however, the treatment for advanced HCC remains unsatisfactory. Here we found that Olaparib, a FDA approved PARP inhibitor, could enhance the cytotoxicity in HCC cells with a lower BRCA1 expression, and suppressing the AR with either Enz or AR-shRNA could further increase the Olaparib sensitivity to better suppress the HCC cell growth via a synergistic mechanism that may involve suppressing the expression of BRCA1 and other DNA damage response (DDR) genes. Mechanism studies revealed that Enz/AR signaling might transcriptional regulting the miR-146a-5p expression via binding to the AREs on its 5 promoter region, which could then lead to suppress the homologous recombination-related BRCA1 expression via direct binding to its 3 UTR of mRNA. Preclinical study using an in vivo mouse model also proved that combined Enz plus Olaparib led to better suppression of the HCC progression. Together, these in vitro/in vivo data suggest that combining Enz and Olaparib may help in the development of a novel therapy to better suppress the HCC progression.