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Title 

Hsp90 inhibition by WK88-1 potently suppresses the growth of gefitinib-resistant H1975 cells harboring the T790M mutation in EGFR

Authors 

Young-Soo HongW J JangK S ChunC H Jeong

Publisher 

Spandidos Publications

Issue Date 

2014

Citation 

Oncology Reports, vol. 31, no. 6, pp. 2619-2624

Keywords 

Drug-resistanceGefitinibHsp90Non-small cell lung cancerWK88-1

Abstract 

Heat shock protein 90 (Hsp90) is a molecular chaperone for numerous client proteins, many of which are crucial for the pathogenesis of non-small cell lung cancers (NSCLCs). To date, therapeutic approaches using epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib or erlotinib for the treatment of NSCLCs have been limited due to the emergence of acquired drug resistance mainly mediated by a secondary T790M mutation in EGFR. Considering this, Hsp90 inhibition seems promising as it leads to overall degradation of the oncogenic EGFR family proteins. In this regard, the present study provides the preclinical basis for a new Hsp90 inhibitor, WK88-1, for the treatment of NSCLCs harboring the T790M mutation in EGFR. Our data revealed that inhibition of Hsp90 by WK88-1 induced overall degradation of multiple oncogenic signaling molecules including EGFR, ErbB2 and ErbB3, leading to subsequent growth arrest and apoptosis in the gefitinib-resistant H1975 cell line. In addition, treatment with WK88-1 markedly inhibited proliferation, migration and invasion in H1975 cells. Moreover, an in vivo xenograft assay indicated that WK88-1 markedly suppressed tumor growth in the H1975 xenografts, highlighting the potential efficacy of WK88-1 for overcoming gefitinib resistance in NSCLCs harboring the T790M mutation in EGFR.

ISSN 

1021-335X

Link 

http://dx.doi.org/10.3892/or.2014.3161

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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