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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

Authors
 Sun Mi Kim  ;  Oh-Joon Kwon  ;  Yun Kyoung Hong  ;  Joo Hang Kim  ;  Flavio Solca  ;  Sang-Jun Ha  ;  Ross A. Soo  ;  James G. Christensen  ;  Ji Hyun Lee  ;  Byoung Chul Cho 
Citation
 Molecular Cancer Therapeutics, Vol.11(10) : 2254-2264, 2012 
Journal Title
 Molecular Cancer Therapeutics 
ISSN
 1535-7163 
Issue Date
2012
Abstract
The 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.
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/91473
DOI
10.1158/1535-7163.MCT-12-0311
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)
Yonsei Authors
권오준(Kwon, Oh Joon) ; 김선미(Kim, Sun Mi) ; 김주항(Kim, Joo Hang) ; 이지현(Lee, Ji Hyun) ; 조병철(Cho, Byoung Chul) ; 홍윤경(Hong, Yun Kyoung)
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Full Text
http://mct.aacrjournals.org/content/11/10/2254
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