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Resistance to gefitinib and cross‐resistance to irreversible EGFR‐TKIs mediated by disruption of the Keap1‐Nrf2 pathway in human lung cancer cells
Author(s) -
Park Seong-Hee,
Kim Jae Hwan,
Ko Eunsun,
Kim Jeong-Yub,
Park Myung-Jin,
Kim Min Jung,
Seo Hyemin,
Li Shibo,
Lee Ji-Yun
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201800011r
Subject(s) - gefitinib , afatinib , cancer research , lung cancer , epidermal growth factor receptor , in vivo , keap1 , tyrosine kinase , cancer , transactivation , osimertinib , biology , medicine , erlotinib , signal transduction , oncology , microbiology and biotechnology , biochemistry , transcription factor , gene
ABSTRACT The development of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) occurs by various mechanisms and appears to be almost inevitable, even in patients with lung cancer who initially respond well to EGFR‐TKIs. Consequently, considerable efforts have been made to develop more effective EGFR‐TKIs. Therefore, an understanding of the mechanisms behind TKI resistance is essential for improving EGFR‐TKI thera peutic efficacy in patients with non‐small cell lung cancer (NSCLC). In this study, we discovered that overexpression of antioxidant‐responsive element (ARE)‐containing Nrf2 target genes by increased transactivation of Nrf2 occurred because of an acquired Keap1 mutation in the gefitinib‐resistant (GR) NSCLC cell line we established. These GR cells also acquired cross‐resistance to the irreversible EGFR‐TKIs, afatinib and osimertinib, and showed increased viability, invasiveness, proliferation, and tumorigenicity both in vitro and in vivo. These results were confirmed by the fact that inhibition of Nrf2 activity, either by treatment with brusatol or by inducing expression of exogenously introduced wild type Keap1, suppressed tumor cell proliferation and tumorigenicity in vitro and in vivo. Our data suggest that disruption of the Keap1‐Nrf2 pathway is one of the mechanisms by which EGFR‐TKI resistance occurs, a fact that must be considered when treating patients with EGFR‐TKI.—Park, S.‐H., Kim, J. H., Ko, E., Kim, J.‐Y., Park, M.‐J., Kim, M. J., Seo, G., Li, S., Lee, J.‐Y. Resistance to gefitinib and cross‐resistance to irreversible EGFR‐TKIs mediated by disruption of the Keap1‐Nrf2 pathway in human lung cancer cells. FASEB J . 32, 5862–5873 (2018). www.fasebj.org