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: 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, Xiujun Cai
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 27 Pg. 41274-41284 (Jul 05 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27129180 (Publication Type: Journal Article)

Chemical References

• PDCD1 protein, human
• Phenylurea Compounds
• Programmed Cell Death 1 Receptor
• Niacinamide
• Sorafenib
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Hep G2 Cells
• Humans
• K562 Cells
• Liver Neoplasms (drug therapy, metabolism, pathology)
• Mice
• Mice, Nude
• Mice, Transgenic
• Niacinamide (analogs & derivatives, therapeutic use)
• Phenylurea Compounds (therapeutic use)
• Phosphorylation (drug effects)
• Programmed Cell Death 1 Receptor (metabolism)
• Signal Transduction (drug effects, physiology)
• Sorafenib