Oncotarget

Research Papers:

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

Shuqun Yang, Chonglin Luo, Qingyang Gu, Qiang Xu, Guan Wang, Hongye Sun, Ziliang Qian, Yexiong Tan, Yuxin Qin, Yuhong Shen, Xiaowei Xu, Shu-Hui Chen, Chi-Chung Chan, Hongyang Wang, Mao Mao and Douglas D. Fang _

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Oncotarget. 2016; 7:5461-5469. https://doi.org/10.18632/oncotarget.6684

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Abstract

Shuqun Yang1, Chonglin Luo1, Qingyang Gu1, Qiang Xu2, Guan Wang2, Hongye Sun2, Ziliang Qian3, Yexiong Tan4, Yuxin Qin1, Yuhong Shen1, Xiaowei Xu5, Shu-Hui Chen6, Chi-Chung Chan1, Hongyang Wang4, Mao Mao7 and Douglas D. Fang1,8

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 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.


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