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Chronic nicotine exposure mediates resistance to EGFR-TKI in EGFR-mutated lung cancer via an EGFR signal.
- Source :
-
Lung cancer (Amsterdam, Netherlands) [Lung Cancer] 2015 Apr; Vol. 88 (1), pp. 16-23. Date of Electronic Publication: 2015 Feb 07. - Publication Year :
- 2015
-
Abstract
- Background: Some of patients with non-small cell lung cancer (NSCLC) harboring somatic activating mutations of the epidermal growth factor receptor gene (EGFR mutations) show poor responses to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) treatment. Cigarette smoking is the strongest documented risk factor for the development of lung cancer. Nicotine, while not carcinogenic by itself, has been shown to induce proliferation, angiogenesis, and the epithelial-mesenchymal transition; these effects might be associated with EGFR-TKI resistance.<br />Materials and Methods: PC-9 and 11&#95;18 cell lines (EGFR-mutated NSCLC cell lines) were cultured with 1μM nicotine for 3 months and were designated as PC-9/N and 11&#95;18/N cell lines, respectively. The sensitivities of these cell lines to EGFR-TKI were then tested in vitro. Moreover, the association between the smoking status and the progression-free survival (PFS) period was investigated in patients with EGFR-mutated NSCLC who were treated with gefitinib.<br />Results: The PC-9/N and 11&#95;18/N cell lines were resistant to EGFR-TKI, compared with controls. The phosphorylation of EGFR in these cell lines was reduced by EGFR-TKI to a smaller extent than that observed in controls, and a higher concentration of EGFR-TKI was capable of further decreasing the phosphorylation. Clinically, smoking history was an independent predictor of a poor PFS period on gefitinib treatment.<br />Conclusions: Chronic nicotine exposure because of cigarette smoking mediates resistance to EGFR-TKI via an EGFR signal. Smoking cessation is of great importance, while resistance may be overcome through the administration of high-dose EGFR-TKI.<br /> (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)
- Subjects :
- Adult
Aged
Aged, 80 and over
Antineoplastic Agents therapeutic use
Carcinoma, Non-Small-Cell Lung genetics
Carcinoma, Non-Small-Cell Lung mortality
Cell Line, Tumor
Disease-Free Survival
ErbB Receptors antagonists & inhibitors
ErbB Receptors metabolism
Female
Gefitinib
Humans
Kaplan-Meier Estimate
Lung Neoplasms genetics
Lung Neoplasms mortality
Male
Middle Aged
Mutation
Quinazolines therapeutic use
Receptors, Nicotinic metabolism
Signal Transduction
Smoking adverse effects
Antineoplastic Agents pharmacology
Carcinoma, Non-Small-Cell Lung drug therapy
Drug Resistance, Neoplasm drug effects
ErbB Receptors genetics
Lung Neoplasms drug therapy
Nicotine pharmacology
Quinazolines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1872-8332
- Volume :
- 88
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Lung cancer (Amsterdam, Netherlands)
- Publication Type :
- Academic Journal
- Accession number :
- 25704955
- Full Text :
- https://doi.org/10.1016/j.lungcan.2015.01.027