Resistance to gefitinib and cross-resistance to irreversible EGFR-TKIs mediated by disruption of the Keap1-Nrf2 pathway in human lung cancer cells

Seong Hee Park, Jae Hwan Kim, Eunsun Ko, Jeong Yub Kim, Myung Jin Park, Min Jung Kim, Hyemin Seo, Shibo Li, Ji-Yun Lee

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 languageEnglish
Pages (from-to)5862-5873
Number of pages12
JournalFASEB Journal
Volume32
Issue number11
DOIs
Publication statusPublished - 2018 Nov 1

Fingerprint

Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Lung Neoplasms
Cells
Non-Small Cell Lung Carcinoma
Transcriptional Activation
Antioxidants
Genes
Mutation
gefitinib
Therapeutics

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 journalArticle

Park, Seong Hee ; Kim, Jae Hwan ; Ko, Eunsun ; Kim, Jeong Yub ; Park, Myung Jin ; Kim, Min Jung ; Seo, Hyemin ; Li, Shibo ; Lee, Ji-Yun. / Resistance to gefitinib and cross-resistance to irreversible EGFR-TKIs mediated by disruption of the Keap1-Nrf2 pathway in human lung cancer cells. In: FASEB Journal. 2018 ; Vol. 32, No. 11. pp. 5862-5873.
@article{f972aeed7f48462f8780b4ed7297bce8,
title = "Resistance to gefitinib and cross-resistance to irreversible EGFR-TKIs mediated by disruption of the Keap1-Nrf2 pathway in human lung cancer cells",
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.",
keywords = "ARE, NFE2L2, NSCLC, Osimertinib",
author = "Park, {Seong Hee} and Kim, {Jae Hwan} and Eunsun Ko and Kim, {Jeong Yub} and Park, {Myung Jin} and Kim, {Min Jung} and Hyemin Seo and Shibo Li and Ji-Yun Lee",
year = "2018",
month = "11",
day = "1",
doi = "10.1096/fj.201800011R",
language = "English",
volume = "32",
pages = "5862--5873",
journal = "The FASEB journal : official publication of the Federation of American Societies for Experimental Biology",
issn = "1530-6860",
publisher = "FASEB",
number = "11",

}

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 -