Sorafenib enriches epithelial cell adhesion... : Hepatology (original) (raw)

Hepatobiliary Malignancies

Sorafenib enriches epithelial cell adhesion molecule–positive tumor initiating cells and exacerbates a subtype of hepatocellular carcinoma through TSC2‐AKT cascade

Guan, Dong‐Xian1; Shi, Jie2; Zhang, Yang3; Zhao, Jiang‐Sha1; Long, Ling‐Yun1; Chen, Tian‐Wei1; Zhang, Er‐Bin1; Feng, Yuan‐Yuan1; Bao, Wen‐Dai1; Deng, Yue‐Zhen1; Qiu, Lin1; Zhang, Xue‐Li4; Koeffler, H. Phillip5,6; Cheng, Shu‐qun*,2; Li, Jing‐Jing*,1; Xie, Dong*,1

1Laboratory of Molecular OncologyInstitute for Nutritional Science, Shanghai Institutes for Biological Sciences, Chinese Academy of SciencesShanghaiChina

2Eastern Hepatobiliary Surgery HospitalSecond Military Medical UniversityShanghaiChina

3The Second Hospital of Anhui Medical UniversityHefeiChina

4Department of General Surgery of FenXian HospitalShanghaiChina

5Cancer Science Institute of SingaporeNational University of SingaporeSingapore

6Division of Hematology/Oncology, Cedars‐Sinai Medical CenterUCLA School of MedicineLos AngelesCA

*Address reprint requests to: Dong Xie or Jing‐Jing Li, Institute of Nutrition Science, Shanghai Institutes for Nutritional Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China. E‐mail: [email protected]; tel: +86‐21‐5492‐0918 (D.X.); E‐mail: [email protected]; tel: +86‐21‐5492‐0918 (J.‐J.L.). Or to: Shuqun Cheng, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai, China. E‐mail: [email protected]; tel: +86‐21‐81875251.

Abstract

Sorafenib is a specific adenosine triphosphate–competitive RAF inhibitor used as a first‐line treatment of advanced hepatocellular carcinoma (HCC). However, the responses are variable, reflecting heterogeneity of the disease, while the resistance mechanism remains poorly understood. Here, we report that sorafenib treatment can exacerbate disease progression in both patient‐derived xenografts and cell line–derived xenografts and that the therapeutic effect of the drug inversely covaries to the ratio of epithelial cell adhesion molecule–positive cells, which may be tumor initiating cells in HCC. The TSC2‐AKT cascade mediates this sorafenib resistance. In response to sorafenib treatment, formation of the TSC1/2 complex is enhanced, causing increased phosphorylation of AKT, which contributes to up‐regulation of “stemness”‐related genes in epithelial cell adhesion molecule–positive cells and enhancement of tumorigenicity. The expression of TSC2 negatively correlated with prognosis in clinical sorafenib therapy. Furthermore, all‐trans retinoic acid decreased AKT activity, reduced the epithelial cell adhesion molecule–positive cell population enriched by sorafenib, and potentiated the therapeutic effect of sorafenib in the patient‐derived xenograft model. Conclusion: Our findings suggest that a subtype of HCC is not suitable for sorafenib therapy; this resistance to sorafenib can be predicted by the status of TSC2, and agents inducing differentiation of tumor initiating cells (e.g., all‐trans retinoic acid) should improve the prognosis of this subtype of HCC.(Hepatology 2015;62:1791–1803)