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.
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.
Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul, Republic of Korea.
Sun Mi
SM
Kim
Oh-Joon
OJ
Kwon
Yun Kyoung
YK
Hong
Joo Hang
JH
Kim
Flavio
F
Solca
Sang-Jun
SJ
Ha
Ross A
RA
Soo
James G
JG
Christensen
Ji Hyun
JH
Lee
Byoung Chul
BC
Cho
D000077716:Afatinib; D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002450:Cell Communication / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D053613:Janus Kinase 1 / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology; D052999:Quinazolinones / Q000737:chemistry / Q000494:pharmacology; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D015850:Interleukin-6; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D052999:Quinazolinones; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; D000077716:Afatinib; C525726:dacomitinib; D066246:ErbB Receptors; D053613:Janus Kinase 1