標題: Non-small-cell lung cancer cells combat epidermal growth factor receptor tyrosine kinase inhibition through immediate adhesion-related responses
作者: Wang, Hsian-Yu
Hsu, Min-Kung
Wang, Kai-Hsuan
Tseng, Ching-Ping
Chen, Feng-Chi
Hsu, John T-A
生物科技學系
分子醫學與生物工程研究所
Department of Biological Science and Technology
Institute of Molecular Medicine and Bioengineering
關鍵字: adhesion response;drug resistance;gene set enrichment analysis;cell stress response
公開日期: 2016
摘要: Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib, and afatinib, have greatly improved treatment efficacy in non-small cell lung cancer (NSCLC) patients with drug-sensitive EGFR mutations. However, in some TKI responders, the benefits of such targeted therapies are limited by the rapid development of resistance, and strategies to overcome this resistance are urgently needed. Studies of drug resistance in cancer cells typically involve long term in vitro induction to obtain stably acquired drug-resistant cells followed by elucidation of resistance mechanisms, but the immediate responses of cancer cells upon drug treatment have been ignored. The aim of this study was to investigate the immediate responses of NSCLC cells upon treatment with EGFR TKIs. Results: Both NSCLC cells, ie, PC9 and H1975, showed immediate enhanced adhesion-related responses as an apoptosis-countering mechanism upon first-time TKI treatment. By gene expression and pathway analysis, adhesion-related pathways were enriched in gefitinib-treated PC9 cells. Pathway inhibition by small-hairpin RNAs or small-molecule drugs revealed that within hours of EGFR TKI treatment, NSCLC cells used adhesion-related responses to combat the drugs. Importantly, we show here that the Src family inhibitor, dasatinib, dramatically inhibits cell adhesion-related response and greatly enhances the cell-killing effects of EGFR TKI (gefitinib for the PC9 cells; afatinib for the H1975 cells) in NSCLC cells, which would otherwise escape the TKI-induced apoptosis. Conclusion: Results from this study indicate that NSCLC cells can employ the adhesion response as a survival pathway to survive under EGFR-targeted therapy. Simultaneous targeting of EGFR signaling and adhesion pathways would further boost the efficacy of EGFR-targeted therapy in NSCLC.
URI: http://dx.doi.org/10.2147/OTT.S96341
http://hdl.handle.net/11536/133845
ISSN: 1178-6930
DOI: 10.2147/OTT.S96341
期刊: ONCOTARGETS AND THERAPY
Volume: 9
起始頁: 2961
結束頁: 2973
顯示於類別:期刊論文