Non-small-cell lung cancer cells combat epidermal growth factor receptor tyrosine kinase inhibition through immediate adhesion-related responses.
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.


CONCLUSIONS
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.
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes (NHRI), Zhunan, Miaoli County, Republic of China; Institute of Molecular Medicine and Bioengineering, National Chiao Tung University (NCTU), Hsinchu, Taiwan, Republic of China.
Hsian-Yu
HY
Wang
Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes (NHRI), Zhunan, Miaoli County, Republic of China; Department of Biological Science and Technology, National Chiao Tung University (NCTU), Hsinchu, Taiwan, Republic of China.
Min-Kung
MK
Hsu
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes (NHRI), Zhunan, Miaoli County, Republic of China.
Kai-Hsuan
KH
Wang
Institute of Molecular Medicine and Bioengineering, National Chiao Tung University (NCTU), Hsinchu, Taiwan, Republic of China; Department of Biological Science and Technology, National Chiao Tung University (NCTU), Hsinchu, Taiwan, Republic of China.
Ching-Ping
CP
Tseng
Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes (NHRI), Zhunan, Miaoli County, Republic of China; Department of Biological Science and Technology, National Chiao Tung University (NCTU), Hsinchu, Taiwan, Republic of China.
Feng-Chi
FC
Chen
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes (NHRI), Zhunan, Miaoli County, Republic of China; Department of Biological Science and Technology, National Chiao Tung University (NCTU), Hsinchu, Taiwan, Republic of China.
John T-A
JT
Hsu
adhesion response; cell stress response; drug resistance; gene set enrichment analysis