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.
journal_name
Oncogenejournal_title
Oncogeneauthors
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 Wdoi
10.1038/s41388-018-0238-8subject
Has Abstractpub_date
2018-07-01 00:00:00pages
3981-3997issue
29eissn
0950-9232issn
1476-5594pii
10.1038/s41388-018-0238-8journal_volume
37pub_type
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