Research Papers:

Sorafenib-resistant hepatocellular carcinoma stratified by phosphorylated ERK activates PD-1 immune checkpoint

Jiang Chen _, Tong Ji, Jie Zhao, Gaofeng Li, Jian Zhang, Renan Jin, Jinghua Liu, Xiaolong Liu, Xiao Liang, Diyu Huang, Anyong Xie, Hui Lin, Yong Cang and Xiujun Cai

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Oncotarget. 2016; 7:41274-41284. https://doi.org/10.18632/oncotarget.8978

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Jiang Chen1,2,*, Tong Ji2,*, Jie Zhao1,2, Gaofeng Li2, Jian Zhang1, Renan Jin1, Jinghua Liu1, Xiaolong Liu1, Xiao Liang1, Diyu Huang1, Anyong Xie1,3, Hui Lin1, Yong Cang2, Xiujun Cai1

1Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China

2Life Sciences Institute and Innovation Center for Cell Signalling Network, Zhejiang University, Hangzhou, Zhejiang, 310029, China

3Institute of Translational Medicine, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310029, China

*These authors have contributed equally to this work

Correspondence to:

Xiujun Cai, e-mail: cxjzu@hotmail.com

Yong Cang, e-mail: cangyong@zju.edu.cn

Hui Lin, e-mail: 369369@zju.edu.cn

Keywords: hepatocellular carcinoma(HCC), phosphorylated extracellular signaling-regulated kinase(pERK), programmed death receptor-1 (PD-1), sorafenib

Received: December 25, 2015     Accepted: March 31, 2016     Published: April 25, 2016


Sorafenib is a multikinase inhibitor approved as the first line treatment for late stage hepatocellular carcinoma (HCC). Due to its significant variation in clinical benefits among patients, defining prognostic biomarkers for sorafenib sensitivity in HCC would allow targeted treatment. Phosphorylated extracellular signaling-regulated kinase (pERK) was proposed to predict the response to sorafenib in HCC, but clinical supports are mixed or even contradictory. Here we found that pERK expression levels are variable in different nodules from individual patient liver. Xenografts derived from resected tumors are resistant to sorafenib inhibition when expressing low levels of pERK. This correlation of low pERK levels and sorafenib resistance is corroborated by histological characterization of chemical-induced and genetic mouse models for pERK-positive and pERK-negative HCC respectively, as well as computed tomography (CT) imaging of patient tumors with validated pERK expression. Mouse and human HCC samples expressing low pERK show strong inflammatory infiltrating cells and significant enrichment of intratumoral CD8+ cytotoxic T lymphocytes that express programmed death receptor-1 (PD-1). These pERK-PD-1+ patients have poorer overall and disease-free survival than pERK+PD-1- patients. In conclusion, our data suggest that anti-PD-1 immunotherapy might complement sorafenib in treating HCC patients by targeting sorafenib-resistant cancer cells, and the dual pERK and PD-1 biomarkers would help HCC patient selection to achieve optimal clinical benefits.

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