Cigarette smoke-induced LKB1/AMPK pathway deficiency reduces EGFR TKI sensitivity in NSCLC
| Autor: | Yu Chun Hsiao, Chih Yen Tu, Chuan-Mu Chen, Hsiao-Fan Chen, Chien Yi Ho, Meng Chieh Yu, Mien Chie Hung, Wei Chien Huang, Te Chun Hsia, Chia-Hung Chen, Dai Wei Hu, Chih Yi Chen, Wen-Chen Tsai, Yung Luen Yu, Chun Yi Wu, Yeh Chen, Chih-Hsin Tang, Wen Yu Chou, Bo Wei Wang, Jennifer L. Hsu, Fang Ju Cheng, Tzong Shiun Li, Ya Ling Wei |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Biology Protein Serine-Threonine Kinases Predictive markers Article Cigarette Smoking 03 medical and health sciences Egfr tki Mice 0302 clinical medicine AMP-Activated Protein Kinase Kinases Carcinoma Non-Small-Cell Lung Cell Line Tumor Genetics Cigarette smoke Animals Humans Glycolysis Protein kinase A Molecular Biology Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Kinase Activator (genetics) TOR Serine-Threonine Kinases Smoking AMPK DNA Methylation Cancer metabolism respiratory tract diseases ErbB Receptors 030104 developmental biology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Mutation Cancer research Heterografts CpG Islands Non-small-cell lung cancer Protein Kinases Signal Transduction |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | Smoker patients with non-small cell lung cancer (NSCLC) have poorer prognosis and survival than those without smoking history. However, the mechanisms underlying the low response rate of those patients to EGFR tyrosine kinase inhibitors (TKIs) are not well understood. Here we report that exposure to cigarette smoke extract enhances glycolysis and attenuates AMP-activated protein kinase (AMPK)-dependent inhibition of mTOR; this in turn reduces the sensitivity of NSCLC cells with wild-type EGFR (EGFRWT) to EGFR TKI by repressing expression of liver kinase B1 (LKB1), a master kinase of the AMPK subfamily, via CpG island methylation. In addition, LKB1 expression is correlated positively with sensitivity to TKI in patients with NSCLC. Moreover, combined treatment of EGFR TKI with AMPK activators synergistically increases EGFR TKI sensitivity. Collectively, the current study suggests that LKB1 may serve as a marker to predict EGFR TKI sensitivity in smokers with NSCLC carrying EGFRWT and that the combination of EGFR TKI and AMPK activator may be a potentially effective therapeutic strategy against NSCLC with EGFRWT. |
| Databáze: | OpenAIRE |
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