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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

Authors
Park, Seong-HeeKim, Jae HwanKo, EunsunKim, Jeong-YubPark, Myung-JinKim, Min JungSeo, HyeminLi, ShiboLee, Ji-Yun
Issue Date
Nov-2018
Publisher
FEDERATION AMER SOC EXP BIOL
Keywords
NSCLC; NFE2L2; ARE; Osimertinib
Citation
FASEB JOURNAL, v.32, no.11, pp.5862 - 5873
Journal Title
FASEB JOURNAL
Volume
32
Number
11
Start Page
5862
End Page
5873
URI
https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/4197
DOI
10.1096/fj.201800011R
ISSN
0892-6638
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 therapeutic 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, H., 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.
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