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

Wei Zhou; Wei Sun; Mingo M.H. Yung; Sheng Dai; Yihua Cai; Chi Wei Chen; Yunxiao Meng; Jennifer B. Lee; John C. Braisted; Yinghua Xu; Noel T. Southall; Paul Shinn; Xuefeng Huang; Zhangfa Song; Xiulei Chen; Yan Kai; Xin Cai; Zongzhu Li; Qiang Hao; Annie N.Y. Cheung; Hextan Y.S. Ngan; Stephanie S. Liu; Stephanie Barak; Jing Hao; Zhijun Dai; Alexandros Tzatsos; Weiqun Peng; Huadong Pei; Zhiyong Han; David W. Chan; Wei Zheng; Wenge Zhu

doi:10.1038/s41388-018-0238-8

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

Wei Zhou
, Wei Sun
, Mingo M.H. Yung
, Sheng Dai
, Yihua Cai
, Chi Wei Chen
, Yunxiao Meng
, Jennifer B. Lee
, John C. Braisted
, Yinghua Xu
, Noel T. Southall
, Paul Shinn
, Xuefeng Huang
, Zhangfa Song
, Xiulei Chen
, Yan Kai
, Xin Cai
, Zongzhu Li
, Qiang Hao
, Annie N.Y. Cheung

Hextan Y.S. Ngan, Stephanie S. Liu, Stephanie Barak, Jing Hao, Zhijun Dai, Alexandros Tzatsos, Weiqun Peng, Huadong Pei, Zhiyong Han, David W. Chan, Wei Zheng, Wenge Zhu

School of Medicine

George Washington University
Zhejiang University
National Institutes of Health
The University of Hong Kong
Xi’an Jiaotong University

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

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.

Original language	English
Pages (from-to)	3981-3997
Number of pages	17
Journal	Oncogene
Volume	37
Issue number	29
DOIs	https://doi.org/10.1038/s41388-018-0238-8
State	Published - 19 Jul 2018

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Zhou, W., Sun, W., Yung, M. M. H., Dai, S., Cai, Y., Chen, C. W., Meng, Y., Lee, J. B., Braisted, J. C., Xu, Y., Southall, N. T., Shinn, P., Huang, X., Song, Z., Chen, X., Kai, Y., Cai, X., Li, Z., Hao, Q., ... Zhu, W. (2018). Autocrine activation of JAK2 by IL-11 promotes platinum drug resistance. Oncogene, 37(29), 3981-3997. https://doi.org/10.1038/s41388-018-0238-8

@article{df5d596114924560932343a45d1acc43,

title = "Autocrine activation of JAK2 by IL-11 promotes platinum drug resistance",

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{\textendash}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{\textendash}JAK2 pathway in platinum-resistant ovarian cancer patients, which highly correlates with poor prognosis. These findings not only identify a novel ROS{\textendash}IL-11{\textendash}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.",

author = "Wei Zhou and Wei Sun and Yung, \{Mingo M.H.\} and Sheng Dai and Yihua Cai and Chen, \{Chi Wei\} and Yunxiao Meng and Lee, \{Jennifer B.\} and Braisted, \{John C.\} and Yinghua Xu and Southall, \{Noel T.\} and Paul Shinn and Xuefeng Huang and Zhangfa Song and Xiulei Chen and Yan Kai and Xin Cai and Zongzhu Li and Qiang Hao and Cheung, \{Annie N.Y.\} and Ngan, \{Hextan Y.S.\} and Liu, \{Stephanie S.\} and Stephanie Barak and Jing Hao and Zhijun Dai and Alexandros Tzatsos and Weiqun Peng and Huadong Pei and Zhiyong Han and Chan, \{David W.\} and Wei Zheng and Wenge Zhu",

note = "Publisher Copyright: {\textcopyright} 2018, Macmillan Publishers Limited, part of Springer Nature.",

year = "2018",

month = jul,

day = "19",

doi = "10.1038/s41388-018-0238-8",

language = "English",

volume = "37",

pages = "3981--3997",

journal = "Oncogene",

issn = "0950-9232",

publisher = "Springer Nature",

number = "29",

}

Zhou, W, Sun, W, Yung, MMH, Dai, S, Cai, Y, Chen, CW, Meng, Y, Lee, JB, Braisted, JC, Xu, Y, Southall, NT, Shinn, P, Huang, X, Song, Z, Chen, X, Kai, Y, Cai, X, Li, Z, Hao, Q, Cheung, ANY, Ngan, HYS, Liu, SS, Barak, S, Hao, J, Dai, Z, Tzatsos, A, Peng, W, Pei, H, Han, Z, Chan, DW, Zheng, W & Zhu, W 2018, 'Autocrine activation of JAK2 by IL-11 promotes platinum drug resistance', Oncogene, vol. 37, no. 29, pp. 3981-3997. https://doi.org/10.1038/s41388-018-0238-8

TY - JOUR

T1 - Autocrine activation of JAK2 by IL-11 promotes platinum drug resistance

AU - Zhou, Wei

AU - Sun, Wei

AU - Yung, Mingo M.H.

AU - Dai, Sheng

AU - Cai, Yihua

AU - Chen, Chi Wei

AU - Meng, Yunxiao

AU - Lee, Jennifer B.

AU - Braisted, John C.

AU - Xu, Yinghua

AU - Southall, Noel T.

AU - Shinn, Paul

AU - Huang, Xuefeng

AU - Song, Zhangfa

AU - Chen, Xiulei

AU - Kai, Yan

AU - Cai, Xin

AU - Li, Zongzhu

AU - Hao, Qiang

AU - Cheung, Annie N.Y.

AU - Ngan, Hextan Y.S.

AU - Liu, Stephanie S.

AU - Barak, Stephanie

AU - Hao, Jing

AU - Dai, Zhijun

AU - Tzatsos, Alexandros

AU - Peng, Weiqun

AU - Pei, Huadong

AU - Han, Zhiyong

AU - Chan, David W.

AU - Zheng, Wei

AU - Zhu, Wenge

PY - 2018/7/19

Y1 - 2018/7/19

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85045461196

U2 - 10.1038/s41388-018-0238-8

DO - 10.1038/s41388-018-0238-8

M3 - Article

C2 - 29662190

AN - SCOPUS:85045461196

SN - 0950-9232

VL - 37

SP - 3981

EP - 3997

JO - Oncogene

JF - Oncogene

IS - 29

ER -

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

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