Reference Detail

Ref Type

Journal Article

PMID

(29812969)

Authors

Park SH, Kim JH, Ko E, Kim JY, Park MJ, Kim MJ, Seo H, Li S, Lee JY

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
FASEB journal : official publication of the Federation of American Societies for Experimental Biology			2018 May 29	fj201800011R	FASEB J

URL

Abstract Text

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 non-small cell lung cancer (NSCLC) patients. 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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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
KEAP1	D236H	missense	loss of function	KEAP1 D236H lies within the BACK domain of the Keap1 protein (UniProt.org). D236H confers a loss of function to the Keap1 protein as demonstrated by loss of Nfe2l2 inhibition leading to nuclear localization of Nfe2l2 in culture (PMID: 17020408), and is associated increased proliferation and migration in culture, tumor growth in animal models, and acquired resistance to tyrosine kinase inhibitors (PMID: 29812969).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KEAP1 D236H	lung non-small cell carcinoma	resistant	Gefitinib	Preclinical - Cell culture	Actionable	In a preclinical study, the KEAP1 D236H mutation was identified in non-small cell lung cancer cells that acquired resistance to Iressa (gefitinib) in culture (PMID: 29812969).	29812969
KEAP1 D236H	lung non-small cell carcinoma	resistant	Afatinib	Preclinical - Cell culture	Actionable	In a preclinical study, non-small cell lung cancer cells that acquired resistance to Iressa (gefitinib) harbored the KEAP1 D236H mutation and also demonstrated resistance to Gilotrif (afatinib) in culture (PMID: 29812969).	29812969
KEAP1 D236H	lung non-small cell carcinoma	resistant	Osimertinib	Preclinical - Cell culture	Actionable	In a preclinical study, non-small cell lung cancer cells that acquired resistance to Iressa (gefitinib) harbored the KEAP1 D236H mutation and also demonstrated resistance to Tagrisso (osimertinib) in culture (PMID: 29812969).	29812969