Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa 920-8641, Japan.
Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa 920-8641, Japan; Department of General Medicine, Kanazawa University Hospital, Kanazawa, Ishikawa 920-8641, Japan.
Cell Mol Gastroenterol Hepatol. 2020;10(2):269-285. doi: 10.1016/j.jcmgh.2020.02.009. Epub 2020 Mar 10.
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.
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.
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.
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.
索拉非尼是一种多受体酪氨酸激酶抑制剂，可延长晚期肝细胞癌（HCC）患者的总生存期。尽管大多数接受索拉非尼治疗的 HCC 患者最终出现疾病进展，但尚不清楚在人类中 HCC 细胞在接受索拉非尼治疗期间是否以及如何获得化疗耐药性。
我们分析了一名接受索拉非尼预防手术后 HCC 复发（辅助索拉非尼治疗肝癌切除或消融试验）的患者手术切除的 HCC 组织，并建立了患者来源的 HCC 细胞。进行全外显子组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对 30 例晚期 HCC 病例进行免疫组织化学检查，并对接受辅助索拉非尼治疗肝癌切除或消融试验的 140 例 HCC 病例进行检查，以评估 Capicua 转录抑制剂（CIC）状态与索拉非尼治疗反应的相关性。
我们在索拉非尼治疗后复发的 HCC 标本中发现了 CIC 突变。CIC 编码 Capicua，是受体酪氨酸激酶信号的通用传感器。从复发性肿瘤标本建立的 HCC 细胞在体外和体内对索拉非尼表现出耐药性。建立的索拉非尼耐药 Huh1 和 Huh7 细胞系显示 Capicua 表达减少而无突变。免疫组织化学分析表明，Capicua 表达低的 HCC 患者总生存期较差。微阵列分析显示，CIC 基因特征可预测辅助索拉非尼治疗对 HCC 复发的预防作用。有趣的是，尽管 CIC 敲低诱导 HCC 细胞系对索拉非尼耐药，但regorafenib 抑制了 Capicua 失活的索拉非尼耐药 HCC 细胞的生长并抑制了细胞外信号调节激酶磷酸化。
评估 Capicua 状态可能对预测索拉非尼的反应至关重要，regorafenib 治疗可能对具有功能性 Capicua 损伤的 HCC 有效。
