Original Research
Inactivation of Transcriptional Repressor Capicua Confers Sorafenib Resistance in Human Hepatocellular Carcinoma

https://doi.org/10.1016/j.jcmgh.2020.02.009Get rights and content
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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.

Keywords

Hepatocellular Carcinoma
Sorafenib
Regorafenib
Capicua

Abbreviations used in this paper

Akt
AKT Serine/Threonine Kinase
B-RAF
V-Raf Murine Sarcoma Viral Oncogene Homolog B
EpCAM
epithelial cell adhesion molecule
ERK
extracellular signal–regulated kinase
ETV4
ETS Variant Transcription Factor 4
HCC
hepatocellular carcinoma
MAPK
mitogen-activated protein kinase
MMP1
Matrix Metallopeptidase 1
MT
metastatic tumor of the liver
NOD/SCID
nonobese diabetic, severe combined immunodeficient
PBMC
peripheral blood mononuclear cell
RFS
recurrence-free survival
RTK
receptor tyrosine kinase
siRNA
small interfering RNA
SR
sorafenib resistance
STAT3
signal transducer and activator of transcription 3
STORM trial
adjuvant sorafenib for hepatocellular carcinoma after resection or ablation trial

Cited by (0)

CRediT Authorship Contributions Tomomi Hashiba (Investigation: Equal; Methodology: Equal; Writing – original draft: Supporting); Taro Yamashita (Conceptualization: Lead; Formal analysis: Equal; Funding acquisition: Lead; Investigation: Equal; Methodology: Equal; Project administration: Lead; Writing – original draft: Lead; Writing – review & editing: Lead); Hikari Okada (Data curation: Lead; Formal analysis: Lead; Investigation: Lead; Methodology: Lead; Writing – review & editing: Supporting); Kouki Nio (Investigation: Supporting; Methodology: Supporting; Resources: Supporting; Writing – review & editing: Supporting); Takehiro Hayashi (Resources: Supporting; Writing – review & editing: Supporting); Yoshiro Asahina (Resources: Supporting; Writing – review & editing: Supporting); Tomoyuki Hayashi (Resources: Supporting; Writing – review & editing: Supporting); Takeshi Terashima (Resources: Supporting; Writing – review & editing: Supporting); Noriho Iida (Resources: Supporting; Writing – review & editing: Supporting); Hajime Takatori (Resources: Supporting; Writing – review & editing: Supporting); Tetsuro Shimakami (Resources: Supporting; Writing – review & editing: Supporting); Kazunori Kawaguchi (Resources: Supporting; Writing – review & editing: Supporting); Kuniaki Arai (Resources: Supporting; Writing – review & editing: Supporting); Yoshio Sakai (Resources: Supporting; Writing – review & editing: Supporting); Tatsuya Yamashita (Resources: Supporting; Writing – review & editing: Supporting); Eishiro Mizukoshi (Resources: Supporting; Writing – review & editing: Supporting); Hiroyuki Takamura (Resources: Supporting; Writing – review & editing: Supporting); Tetsuo Ohta (Resources: Supporting; Writing – review & editing: Supporting); Masao Honda (Data curation: Equal; Resources: Supporting; Visualization: Supporting; Writing – review & editing: Supporting); Shuichi Kaneko (Supervision: Lead; Writing – review & editing: Supporting).

Conflicts of interest This author discloses the following: Shuichi Kaneko received a research grant from Bayer, the manufacturer of sorafenib and regorafenib. The remaining authors disclosed no conflicts.

Funding This study was supported by grants from the Joint Research in East Asia (16934588), the Japanese Ministry of Education, Culture, Sports, Science and Technology (18H02792, 18K19538, and 16671907), Practical Research for Innovative Cancer Control (18970618), Program for Basic and Clinical Research on Hepatitis of Japan Agency for Medical Research and Development (17929612), the CHOZEN project, and a research grant from Bayer.

§

Authors share co-senior authorship.