한빛사 논문
연세대학교
Sun Mi Kim1,6, Oh-Joon Kwon4, Yun Kyoung Hong1,6, Joo Hang Kim1,2, Flavio Solca7, Sang-Jun Ha5, Ross A. Soo8, James G. Christensen9, Ji Hyun Lee3,*, and Byoung Chul Cho1,2,*
1Institute for Cancer Research, Yonsei Cancer Center;
2Departments of Internal Medicine, and 3Pharmacology, Pharmacogenomic Research Center for Membrane Transporters and Research Center for Human Natural Defense System, Yonsei University College of Medicine;
4National Core Research Center for Nanomedical Technology;
5Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul;
6JE UK Institute for Cancer Research, JE UK Chemical Company, Gumi-City, Kyungbuk, Republic of Korea;
7Department of Pharmacology, Boehringer Ingelheim Austria, Vienna, Austria;
8Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Cancer Science Institute of Singapore, National University of Singapore, Singapore;
9Department of Cancer Research, Pfizer Global Research and Development, La Jolla Laboratories, La Jolla, California
*Corresponding author
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.
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