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Autocrine activation of JAK2 by IL-11 promotes platinum drug resistance

Oncogene volume 37, pages 3981–3997 (2018)Cite this article

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Abstract

Antineoplastic platinum agents are used in first-line treatment of ovarian cancer, but treatment failure frequently results from platinum drug resistance. Emerging observations suggest a role of reactive oxygen species (ROS) in the resistance of cancer drugs including platinum drugs. However, the molecular link between ROS and cellular survival pathway is poorly understood. Using quantitative high-throughput combinational screen (qHTCS) and genomic sequencing, we show that in platinum-resistant ovarian cancer elevated ROS levels sustain high level of IL-11 by stimulating FRA1-mediated IL-11 expression and increased IL-11 causes resistance to platinum drugs by constitutively activating JAK2–STAT5 via an autocrine mechanism. Inhibition of JAK2 by LY2784544 or IL-11 by anti-IL-11 antibody overcomes the platinum resistance in vitro or in vivo. Significantly, clinic studies also confirm the activated IL-11–JAK2 pathway in platinum-resistant ovarian cancer patients, which highly correlates with poor prognosis. These findings not only identify a novel ROS–IL-11–JAK2-mediated platinum resistance mechanism but also provide a new strategy for using LY2784544- or IL-11-mediated immunotherapy to treat platinum-resistant ovarian cancer.

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Acknowledgements

This work was partially supported by funding from the National Institutes of Health (CA177898 and CA184717 to W. Zhu), the McCormick Genomic and Proteomic Center, and intramural research program at the National Center for Advancing Translational Sciences (NCATS). W Zhu was supported by a Research Scholar Grant, RSG-13-214-01-DMC from the American Cancer Society. This work was supported by the National Natural Science Foundation of China grant 81402580 to W Zhou.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA

    Wei Zhou, Yihua Cai, Chi-Wei Chen, Yunxiao Meng, Jennifer B. Lee, Xin Cai, Zongzhu Li, Qiang Hao, Jing Hao, Huadong Pei, Zhiyong Han & Wenge Zhu

  2. Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China

    Wei Zhou, Sheng Dai, Xuefeng Huang & Zhangfa Song

  3. GW Cancer Centre, The George Washington University, Washington, DC, 20052, USA

    Wei Zhou, Yihua Cai, Chi-Wei Chen, Yunxiao Meng, Jennifer B. Lee, Yan Kai, Xin Cai, Zongzhu Li, Qiang Hao, Alexandros Tzatsos, Huadong Pei & Wenge Zhu

  4. National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20892, USA

    Wei Sun, Sheng Dai, John C. Braisted, Noel T. Southall, Paul Shinn & Wei Zheng

  5. Department of Obstetrics and Gynecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Mingo M. H. Yung & David W. Chan

  6. Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China

    Yinghua Xu

  7. Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China

    Xiulei Chen

  8. Department of Physics, The George Washington University Columbian College of Arts & Sciences, Washington, DC, 20052, USA

    Yan Kai & Weiqun Peng

  9. Department of Pathology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Annie N. Y. Cheung, Hextan Y. S. Ngan & Stephanie S. Liu

  10. Department of Pathology, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA

    Stephanie Barak

  11. Department of Oncology, the Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, 710004, China

    Zhijun Dai

  12. Department of Anatomy and Regenerative Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA

    Alexandros Tzatsos

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  1. Wei Zhou
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Correspondence to David W. Chan, Wei Zheng or Wenge Zhu.

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These authors contributed equally: Wei Zhou, Wei Sun.

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Zhou, W., Sun, W., Yung, M.M.H. et al. Autocrine activation of JAK2 by IL-11 promotes platinum drug resistance. Oncogene 37, 3981–3997 (2018). https://doi.org/10.1038/s41388-018-0238-8

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