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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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.
Conflict of interest
The authors declare that they have no conflict of interest.
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) doi:10.1038/s41388-018-0238-8
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