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|Title:||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:||Kim, S.M.
|Issue Date:||Oct-2012||Citation:||Kim, S.M., Kwon, O.-J., Hong, Y.K., Kim, J.H., Solca, F., Ha, S.-J., Soo, R.A., Christensen, J.G., Lee, J.H., Cho, B.C. (2012-10). 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. Molecular Cancer Therapeutics 11 (10) : 2254-2264. ScholarBank@NUS Repository. https://doi.org/10.1158/1535-7163.MCT-12-0311||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. ©2012 AACR.||Source Title:||Molecular Cancer Therapeutics||URI:||http://scholarbank.nus.edu.sg/handle/10635/116210||ISSN:||15357163||DOI:||10.1158/1535-7163.MCT-12-0311|
|Appears in Collections:||Staff Publications|
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