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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

 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 
 Molecular Cancer Therapeutics, Vol.11(10) : 2254-2264, 2012 
Journal Title
 Molecular Cancer Therapeutics 
Issue Date
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.
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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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