title: Sorafenib-resistant hepatocellular carcinoma stratified by phosphorylated ERK activates PD-1 immune checkpoint.
abstract: 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.
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.|Life Sciences Institute and Innovation Center for Cell Signalling Network, Zhejiang University, Hangzhou, Zhejiang, 310029, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Chen
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signalling Network, Zhejiang University, Hangzhou, Zhejiang, 310029, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Ji
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.|Life Sciences Institute and Innovation Center for Cell Signalling Network, Zhejiang University, Hangzhou, Zhejiang, 310029, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signalling Network, Zhejiang University, Hangzhou, Zhejiang, 310029, China.
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
authors.forename: Renan
authors.initials: R
authors.lastname: Jin
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
authors.forename: Diyu
authors.initials: D
authors.lastname: Huang
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.|Institute of Translational Medicine, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310029, China.
authors.forename: Anyong
authors.initials: A
authors.lastname: Xie
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Lin
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signalling Network, Zhejiang University, Hangzhou, Zhejiang, 310029, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Cang
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
authors.forename: Xiujun
authors.initials: X
authors.lastname: Cai
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D020014:K562 Cells; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000077157:Sorafenib
chemical_list: C105992:PDCD1 protein, human; D010671:Phenylurea Compounds; D061026:Programmed Cell Death 1 Receptor; D009536:Niacinamide; D000077157:Sorafenib; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: hepatocellular carcinoma(HCC); phosphorylated extracellular signaling-regulated kinase(pERK); programmed death receptor-1 (PD-1); sorafenib