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Activation of IL-6R/JAK1/STAT3 signaling induces de novo resistance to irreversible EGFR inhibitors in non-small cell lung cancer with T790M resistance mutation

DC FieldValueLanguage
dc.contributor.author홍윤경-
dc.contributor.author권오준-
dc.contributor.author김선미-
dc.contributor.author김주항-
dc.contributor.author이지현-
dc.contributor.author조병철-
dc.date.accessioned2014-12-19T17:28:24Z-
dc.date.available2014-12-19T17:28:24Z-
dc.date.issued2012-
dc.identifier.issn1535-7163-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/91473-
dc.description.abstractThe secondary T790M mutation in epidermal growth factor receptor (EGFR) is the major mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (TKI) in non-small cell lung cancer (NSCLC). Although irreversible EGFR TKIs, such as afatinib or dacomitinib, have been introduced to overcome the acquired resistance, they showed a limited efficacy in NSCLC with T790M. Herein, we identified the novel de novo resistance mechanism to irreversible EGFR TKIs in H1975 and PC9-GR cells, which are NSCLC cells with EGFR T790M. Afatinib activated interleukin-6 receptor (IL-6R)/JAK1/STAT3 signaling via autocrine IL-6 secretion in both cells. Inhibition of IL-6R/JAK1/STAT3 signaling pathway increased the sensitivity to afatinib. Cancer cells showed stronger STAT3 activation and enhanced resistance to afatinib in the presence of MRC5 lung fibroblasts. Blockade of IL-6R/JAK1 significantly increased the sensitivity to afatinib through inhibition of afatinib-induced STAT3 activation augmented by the interaction with fibroblasts, suggesting a critical role of paracrine IL-6R/JAK1/STAT3 loop between fibroblasts and cancer cells in the development of drug resistance. The enhancement of afatinib sensitivity by inhibition of IL-6R/JAK1/STAT3 signaling was confirmed in in vivo PC9-GR xenograft model. Similar to afatinib, de novo resistance to dacomitinib in H1975 and PC9-GR cells was also mediated by dacomitinib-induced JAK1/STAT3 activation. Taken together, these findings suggest that IL-6R/JAK1/STAT3 signaling can be a potential therapeutic target to enhance the efficacy of irreversible EGFR TKIs in patients with EGFR T790M.-
dc.description.statementOfResponsibilityopen-
dc.relation.isPartOfMolecular Cancer Therapeutics-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/2.0/kr/-
dc.titleActivation of IL-6R/JAK1/STAT3 signaling induces de novo resistance to irreversible EGFR inhibitors in non-small cell lung cancer with T790M resistance mutation-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentMedical Research Center (임상의학연구센터)-
dc.contributor.googleauthorSun Mi Kim-
dc.contributor.googleauthorOh-Joon Kwon-
dc.contributor.googleauthorYun Kyoung Hong-
dc.contributor.googleauthorJoo Hang Kim-
dc.contributor.googleauthorFlavio Solca-
dc.contributor.googleauthorSang-Jun Ha-
dc.contributor.googleauthorRoss A. Soo-
dc.contributor.googleauthorJames G. Christensen-
dc.contributor.googleauthorJi Hyun Lee-
dc.contributor.googleauthorByoung Chul Cho-
dc.identifier.doi10.1158/1535-7163.MCT-12-0311-
dc.admin.authorfalse-
dc.admin.mappingfalse-
dc.contributor.localIdA04423-
dc.contributor.localIdA00236-
dc.contributor.localIdA00945-
dc.contributor.localIdA03822-
dc.contributor.localIdA00546-
dc.contributor.localIdA03217-
dc.relation.journalcodeJ02254-
dc.identifier.urlhttp://mct.aacrjournals.org/content/11/10/2254-
dc.contributor.alternativeNameHong, Yun Kyoung-
dc.contributor.alternativeNameKwon, Oh Joon-
dc.contributor.alternativeNameKim, Sun Mi-
dc.contributor.alternativeNameKim, Joo Hang-
dc.contributor.alternativeNameLee, Ji Hyun-
dc.contributor.alternativeNameCho, Byoung Chul-
dc.contributor.affiliatedAuthorHong, Yun Kyoung-
dc.contributor.affiliatedAuthorKwon, Oh Joon-
dc.contributor.affiliatedAuthorKim, Joo Hang-
dc.contributor.affiliatedAuthorCho, Byoung Chul-
dc.contributor.affiliatedAuthorKim, Sun Mi-
dc.contributor.affiliatedAuthorLee, Ji Hyun-
dc.citation.volume11-
dc.citation.number10-
dc.citation.startPage2254-
dc.citation.endPage2264-
dc.identifier.bibliographicCitationMolecular Cancer Therapeutics, Vol.11(10) : 2254-2264, 2012-
Appears in Collections:
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Medical Research Center (임상의학연구센터)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실)
1. Journal Papers (연구논문) > 5. Research Institutes (연구소) > Research Center for Human Natural Defense System (생체방어연구센터)

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