title: Activating JAK1 mutation may predict the sensitivity of JAK-STAT inhibition in hepatocellular carcinoma.
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 JAK1S703I 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 JAK1S703I 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 JAK1S703I 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.
authors.affiliation: Oncology Business Unit, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China.
authors.forename: Shuqun
authors.initials: S
authors.lastname: Yang
authors.affiliation: Oncology Business Unit, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China.
authors.forename: Chonglin
authors.initials: C
authors.lastname: Luo
authors.affiliation: Oncology Business Unit, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China.
authors.forename: Qingyang
authors.initials: Q
authors.lastname: Gu
authors.affiliation: Genome Center, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Genome Center, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China.
authors.forename: Guan
authors.initials: G
authors.lastname: Wang
authors.affiliation: Genome Center, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China.
authors.forename: Hongye
authors.initials: H
authors.lastname: Sun
authors.affiliation: Shanghai Johnson & Johnson Pharmaceuticals Ltd., Shanghai, China.
authors.forename: Ziliang
authors.initials: Z
authors.lastname: Qian
authors.affiliation: Eastern Hepatobiliary Surgery Hospital/Institute of Shanghai, Shanghai, China.
authors.forename: Yexiong
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Oncology Business Unit, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Oncology Business Unit, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Xu
authors.affiliation: Domestic Discovery Service Unit, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China.
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Oncology Business Unit, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China.
authors.forename: Chi-Chung
authors.initials: CC
authors.lastname: Chan
authors.affiliation: Eastern Hepatobiliary Surgery Hospital/Institute of Shanghai, Shanghai, China.
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
authors.affiliation: Translational Bioscience and Diagnostics, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China.
authors.forename: Mao
authors.initials: M
authors.lastname: Mao
authors.affiliation: Oncology Business Unit, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China.|Current address: Cancer Translational Research, China Novartis Institute for Biomedical Research, Shanghai, China.
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Fang
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics*; D009570:Nitriles; D010766:Phosphorylation; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C540383:ruxolitinib; C507904:JAK1 protein, human; D053613:Janus Kinase 1
keywords: HCC; JAK1; PDX; ruxolitinib