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bioRxiv · 10.1101/712315

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

Zhao, J.·Sun, Y.·Lin, H.·Chou, F.·Xiao, Y.·Jin, R.·Cai, X.·Chang, C.
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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.

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Zhao, J., Sun, Y., Lin, H., Chou, F., Xiao, Y., Jin, R., Cai, X., Chang, C.. 2019-07-23. Olaparib and Enzalutamide synergistically suppress HCC progression via the AR-mediated miR-146a-5p/BRCA1 signaling. https://doi.org/10.1101/712315

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