Background & Aims

Sorafenib is a multireceptor tyrosine kinase inhibitor that can prolong overall survival in patients with advanced hepatocellular carcinoma (HCC). Although most HCC patients who receive sorafenib ultimately show disease progression, it still is unclear whether and how HCC cells acquire chemoresistance during sorafenib treatment in human beings.

Methods

We analyzed surgically resected HCC tissues from a patient who received sorafenib for prevention of HCC recurrence after surgery (Adjuvant Sorafenib for Hepatocellular Carcinoma after Resection or Ablation 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 Adjuvant Sorafenib for Hepatocellular Carcinoma after Resection or Ablation trial using microarray analysis to evaluate the association of Capicua Transcriptional Repressor (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 receptor tyrosine kinase signaling. HCC cells established from the recurrent tumor specimen showed 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 showed 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.

中文翻译：

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转录抑制因子Capicua的失活赋予人类肝细胞癌索拉非尼耐药性。

背景与目标

索拉非尼是一种多受体酪氨酸激酶抑制剂，可以延长晚期肝细胞癌（HCC）患者的总生存期。尽管大多数接受索拉非尼的HCC患者最终都显示出疾病进展，但仍不清楚在人类索拉非尼治疗期间HCC细胞是否以及如何获得化学抗性。

方法

我们分析了接受索拉非尼预防手术后肝癌复发的患者的手术切除的肝癌组织（切除或消融试验后佐拉非尼用于肝细胞癌的辅助治疗），并建立了患者衍生的肝癌细胞。进行全外显子序列分析以检测索拉非尼耐药克隆中的突变。我们使用微阵列分析评估了切除或消融试验后的30例晚期肝癌的免疫组织化学结果和140例肝癌的索拉非尼佐剂登记的肝癌病例，以评估Capicua转录抑制因子（CIC）状态与索拉非尼治疗反应的相关性。

结果

我们在索拉非尼后的复发性HCC标本中发现了CIC突变。CIC编码Capicua，一种受体酪氨酸激酶信号转导的通用传感器。从复发性肿瘤标本中建立的HCC细胞在体外和体内均显示出对索拉非尼的化学耐药性。建立的索拉非尼耐药的Huh1和Huh7细胞系显示Capicua的表达减少而无突变。免疫组织化学分析显示，Capicua低表达的HCC患者的总生存期较差。芯片分析表明，CIC基因标记可以预测索拉非尼辅助治疗对肝癌复发的预防作用。有趣的是，尽管CIC 击倒诱导HCC细胞系中的索拉非尼耐药，雷戈非尼抑制了对索拉非尼耐药，Capicua灭活的HCC细胞的生长，并抑制了细胞外信号调节的激酶磷酸化。

结论

Capicua状况的评估对于预测对索拉非尼的反应可能至关重要，而雷戈非尼治疗可能有效治疗功能性Capicua受损的HCC。