國家衛生研究院 NHRI:Item 3990099045/12986

NHRI > Institute of Biotechnology and Pharmaceutical Research > Chiung-Tong Chen > Periodical Articles > Item 3990099045/12986

Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/12986

Title:	Molecular profiling of afatinib-resistant non-small cell lung cancer cells in vivo derived from mice
Authors:	Chung, CT;Yeh, KC;Lee, CH;Chen, YY;Ho, PJ;Chang, KY;Chen, CH;Lai, YK;Chen, CT
Contributors:	Institute of Biotechnology and Pharmaceutical Research;National Institute of Cancer Research
Abstract:	Non-small-cell lung cancer (NSCLC) is a leading cause of cancer-related death worldwide. NSCLC patients with overexpressed or mutated epidermal growth factor receptor (EGFR) related to disease progression are treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Acquired drug resistance after TKI treatments has been a major focus for development of NSCLC therapies. This study aimed to establish afatinib-resistant cell lines from which afatinib resistance-associated genes are identified and the underlying mechanisms of multiple-TKI resistance in NSCLC can be further investigated. Nude mice bearing subcutaneous NSCLC HCC827 tumors were administered with afatinib at different dose intensities (5-100 mg/kg). We established three HCC827 sublines resistant to afatinib (IC(50) > 1 µM) with cross-resistance to gefitinib (IC(50) > 5 µM). cDNA microarray revealed several of these sublines shared 27 up- and 13 down-regulated genes. The mRNA expression of selective novel genes - such as transmembrane 4 L six family member 19 (TM4SF19), suppressor of cytokine signaling 2 (SOCS2), and quinolinate phosphoribosyltransferase (QPRT) - are responsive to afatinib treatments only at high concentrations. Furthermore, c-MET amplification and activations of a subset of tyrosine kinase receptors were observed in all three resistant cells. PHA665752, a c-MET inhibitor, remarkably increased the sensitivity of these resistant cells to afatinib (IC(50) = 12-123 nM). We established afatinib-resistant lung cancer cell lines and here report genes associated with afatinib resistance in human NSCLC. These cell lines and the identified genes serve as useful investigational tools, prognostic biomarkers of TKI therapies, and promising molecule targets for development of human NSCLC therapeutics.
Date:	2020-11
Relation:	Pharmacological Research. 2020 Nov;161:Article number 105183.
Link to:	http://dx.doi.org/10.1016/j.phrs.2020.105183
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1043-6618&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000600990100052
Cited Times(Scopus):	https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85095580548
Appears in Collections:	[Chiung-Tong Chen] Periodical Articles [Chia-Huei Lee] Periodical Articles

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