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 respondwell toEGFR-TKIs.Consequently, considerable effortshavebeenmadeto developmore effectiveEGFR-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 linewe 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 wildtype Keap1, suppressed tumorcell proliferationandtumorigenicity in vitroandin 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 consideredwhen treatingpatientswithEGFR-TKI.
| Original language | English |
|---|---|
| Pages (from-to) | 5862-5873 |
| Number of pages | 12 |
| Journal | FASEB Journal |
| Volume | 32 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - 2018 Nov 1 |
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Keywords
- ARE
- NFE2L2
- NSCLC
- Osimertinib
ASJC Scopus subject areas
- Biotechnology
- Biochemistry
- Molecular Biology
- Genetics
Cite this
Resistance to gefitinib and cross-resistance to irreversible EGFR-TKIs mediated by disruption of the Keap1-Nrf2 pathway in human lung cancer cells. / Park, Seong Hee; Kim, Jae Hwan; Ko, Eunsun; Kim, Jeong Yub; Park, Myung Jin; Kim, Min Jung; Seo, Hyemin; Li, Shibo; Lee, Ji-Yun.
In: FASEB Journal, Vol. 32, No. 11, 01.11.2018, p. 5862-5873.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Resistance to gefitinib and cross-resistance to irreversible EGFR-TKIs mediated by disruption of the Keap1-Nrf2 pathway in human lung cancer cells
AU - Park, Seong Hee
AU - Kim, Jae Hwan
AU - Ko, Eunsun
AU - Kim, Jeong Yub
AU - Park, Myung Jin
AU - Kim, Min Jung
AU - Seo, Hyemin
AU - Li, Shibo
AU - Lee, Ji-Yun
PY - 2018/11/1
Y1 - 2018/11/1
N2 - 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 respondwell toEGFR-TKIs.Consequently, considerable effortshavebeenmadeto developmore effectiveEGFR-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 linewe 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 wildtype Keap1, suppressed tumorcell proliferationandtumorigenicity in vitroandin 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 consideredwhen treatingpatientswithEGFR-TKI.
AB - 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 respondwell toEGFR-TKIs.Consequently, considerable effortshavebeenmadeto developmore effectiveEGFR-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 linewe 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 wildtype Keap1, suppressed tumorcell proliferationandtumorigenicity in vitroandin 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 consideredwhen treatingpatientswithEGFR-TKI.
KW - ARE
KW - NFE2L2
KW - NSCLC
KW - Osimertinib
UR - http://www.scopus.com/inward/record.url?scp=85055819703&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85055819703&partnerID=8YFLogxK
U2 - 10.1096/fj.201800011R
DO - 10.1096/fj.201800011R
M3 - Article
AN - SCOPUS:85055819703
VL - 32
SP - 5862
EP - 5873
JO - The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
JF - The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
SN - 1530-6860
IS - 11
ER -