Activating JAK1 mutation may predict the sensitivity of JAK-STAT inhibition in hepatocellular carcinoma

// Shuqun Yang 1 , Chonglin Luo 1 , Qingyang Gu 1 , Qiang Xu 2 , Guan Wang 2 , Hongye Sun 2 , Ziliang Qian 3 , Yexiong Tan 4 , Yuxin Qin 1 , Yuhong Shen 1 , Xiaowei Xu 5 , Shu-Hui Chen 6 , Chi-Chung Chan 1 , Hongyang Wang 4 , Mao Mao 7 and Douglas D. Fang 1,8 1 Oncology Business Unit, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China 2 Genome Center, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China 3 Shanghai Johnson & Johnson Pharmaceuticals Ltd., Shanghai, China 4 Eastern Hepatobiliary Surgery Hospital/Institute of Shanghai, Shanghai, China 5 Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA 6 Domestic Discovery Service Unit, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China 7 Translational Bioscience and Diagnostics, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China 8 Current address: Cancer Translational Research, China Novartis Institute for Biomedical Research, Shanghai, China Correspondence to: Mao Mao, email: // Douglas D. Fang, email: // Keywords : HCC, PDX, JAK1, ruxolitinib Received : March 27, 2015 Accepted : December 09, 2015 Published : December 19, 2015 Abstract Hepatocellular carcinoma (HCC) is the fifth most common type of cancers worldwide. However, current therapeutic approaches for this epidemic disease are limited, and its 5-year survival rate hasn’t been improved in the past decades. Patient-derived xenograft (PDX) tumor models have become an excellent in vivo system for understanding of disease biology and drug discovery. In order to identify new therapeutic targets for HCC, whole-exome sequencing (WES) was performed on more than 60 HCC PDX models. Among them, four models exhibited protein-altering mutations in JAK1 (Janus Kinase 1) gene. To explore the transforming capability, these mutations were then introduced into HEK293FT and Ba/F3 cells. The results demonstrated that JAK1 S703I mutation was able to activate JAK-STAT (Signal Transducer and Activator of Transcription) signaling pathway and drive cell proliferation in the absence of cytokine stimulation in vitro . Furthermore,the sensitivity to the treatment of a JAK1/2 inhibitor, ruxolitinib, was observed in JAK1 S703I mutant PDX model, but not in other non-activating mutant or wild type models. Pharmacodynamic analysis showed that phosphorylation of STAT3 in the Ruxolitinib-treated tumor tissues was significantly suppressed. Collectively, our results suggested that JAK1 S703I is an activating mutation for JAK-STAT signaling pathway in vitro and in vivo , and JAK-STAT pathway might represent a new therapeutic approach for HCC treatment. Monotherapy using a more potent and specific JAK1 inhibitor and combinatory therapy should be further explored in JAK1 mutant PDX models.