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

TitleAutocrine activation of JAK2 by IL-11 promotes platinum drug resistance
Authors
Issue Date2018
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
Citation
Oncogene, 2018, v. 37, p. 3981-3997 How to Cite?
AbstractAntineoplastic 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.
Persistent Identifierhttp://hdl.handle.net/10722/252700
ISSN
2017 Impact Factor: 6.854
2015 SCImago Journal Rankings: 4.047
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorZhou, W-
dc.contributor.authorSun, W-
dc.contributor.authorYung, MH-
dc.contributor.authorDai, S-
dc.contributor.authorCai, Y-
dc.contributor.authorChen, CW-
dc.contributor.authorMeng, Y-
dc.contributor.authorLee, JB-
dc.contributor.authorBraisted, JC-
dc.contributor.authorXu, Y-
dc.contributor.authorSouthall, NT-
dc.contributor.authorShinn, P-
dc.contributor.authorHuang, X-
dc.contributor.authorSong, Z-
dc.contributor.authorChen, X-
dc.contributor.authorKai, Y-
dc.contributor.authorCai, X-
dc.contributor.authorLi, Z-
dc.contributor.authorHao, Q-
dc.contributor.authorCheung, ANY-
dc.contributor.authorNgan, HYS-
dc.contributor.authorLiu, S-
dc.contributor.authorBarak, S-
dc.contributor.authorHao, J-
dc.contributor.authorDai, Z-
dc.contributor.authorTzatsos, A-
dc.contributor.authorPeng, W-
dc.contributor.authorPei, H-
dc.contributor.authorHan, Z-
dc.contributor.authorChan, DW-
dc.contributor.authorZheng, W-
dc.contributor.authorZhu, W-
dc.date.accessioned2018-04-30T08:44:23Z-
dc.date.available2018-04-30T08:44:23Z-
dc.date.issued2018-
dc.identifier.citationOncogene, 2018, v. 37, p. 3981-3997-
dc.identifier.issn0950-9232-
dc.identifier.urihttp://hdl.handle.net/10722/252700-
dc.description.abstractAntineoplastic 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.-
dc.languageeng-
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc-
dc.relation.ispartofOncogene-
dc.titleAutocrine activation of JAK2 by IL-11 promotes platinum drug resistance-
dc.typeArticle-
dc.identifier.emailYung, MH: mhyung@hku.hk-
dc.identifier.emailCheung, ANY: anycheun@hkucc.hku.hk-
dc.identifier.emailNgan, HYS: hysngan@hkucc.hku.hk-
dc.identifier.emailLiu, S: stephasl@hku.hk-
dc.identifier.emailChan, DW: dwchan@hku.hk-
dc.identifier.authorityCheung, ANY=rp00542-
dc.identifier.authorityNgan, HYS=rp00346-
dc.identifier.authorityLiu, S=rp00372-
dc.identifier.authorityChan, DW=rp00543-
dc.description.naturepostprint-
dc.identifier.doi10.1038/s41388-018-0238-8-
dc.identifier.hkuros284933-
dc.identifier.volume37-
dc.identifier.spage3981-
dc.identifier.epage3997-
dc.identifier.isiWOS:000439101300006-
dc.publisher.placeUnited Kingdom-

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