Inactivation of transcriptional repressor Capicua confers sorafenib-resistance in human hepatocellular carcinoma.

Abstract Background and Aims Sorafenib is a multi-receptor tyrosine kinase (RTK) inhibitor that can prolong overall survival in patients with advanced hepatocellular carcinoma (HCC). Although most HCC patients who receive sorafenib ultimately exhibit disease progression, it is still unclear whether and how HCC cells acquire chemoresistance during sorafenib treatment in humans. Methods We analyzed surgically resected HCC tissues from a patient who received sorafenib for prevention of HCC recurrence after surgery (STORM trial) and established patient-derived HCC cells. Whole exome sequence analysis was performed to detect mutations in sorafenib-resistant clones. We examined 30 advanced HCC cases immunohistochemically and 140 HCC cases enrolled in the STORM trial using microarray analysis to evaluate association of CIC status with sorafenib treatment response. Results We found a CIC mutation in recurrent HCC specimens after sorafenib. CIC encodes Capicua, a general sensor of RTK signaling. HCC cells established from the recurrent tumor specimen exhibited chemoresistance to sorafenib in vitro and in vivo. Established sorafenib-resistant Huh1 and Huh7 cell lines showed reduced expression of Capicua without mutations. Immunohistochemical analysis revealed that HCC patients with low Capicua expression showed poor overall survival. Microarray analysis showed that the CIC gene signature could predict the preventive effect of adjuvant sorafenib treatment on HCC recurrence. Intriguingly, although CIC knockdown induced sorafenib-resistance in HCC cell lines, regorafenib suppressed growth of sorafenib-resistant Capicua-inactivated HCC cells and inhibited extracellular signal-regulated kinase phosphorylation. Conclusions Evaluation of Capicua status may be pivotal to predict response to sorafenib, and regorafenib treatment could be effective to treat HCC with functional Capicua impairment.