Sonic hedgehog signalling pathway contributes to sorafenib resistance in liver cancer

Abstract

Liver cancer, primarily hepatocellular carcinoma (HCC), is a leading cause of cancer-related deaths worldwide. Currently, sorafenib is the only FDA-approved drug for treating advanced HCC. However, the efficacy of sorafenib on overall survival in HCC patients appears to be low due to primary and acquired resistance mechanisms, which remain poorly understood. To further understand the underlying molecular mechanisms of sorafenib resistance, we used genome-scale CRISPR/Cas9 knockout screening in human HCC cells and identified GLI1, a key downstream effector of the Sonic Hedgehog signalling pathway, as a potential mediator of sorafenib resistance in HCC.

Our clinical data showed that GLI1 was frequently upregulated in HCC and overexpression of GLI1 was associated with poorer overall survival in HCC patients. Functionally, we found that knockdown and knockout of GLI1 sensitised HCC cells to sorafenib treatment both in vitro and in vivo through increased apoptosis. In addition, co-treatment of a specific GLI1 inhibitor, GANT61, and sorafenib significantly induced apoptosis and suppressed tumour growth. Taken together, these findings suggest that aberrant activation of Sonic Hedgehog signalling pathway is linked to sorafenib resistance in HCC and there may be a potential therapeutic value of combinatorial therapy of Sonic Hedgehog signalling inhibitors and sorafenib for HCC management.