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 journalArticlepeer-review

    24 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

    Keywords

    • ARE
    • NFE2L2
    • NSCLC
    • Osimertinib

    ASJC Scopus subject areas

    • Biotechnology
    • Biochemistry
    • Molecular Biology
    • Genetics

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