Src Mediates Cigarette Smoke–Induced Resistance to Tyrosine Kinase Inhibitors in NSCLC Cells
Autor: | Tzipora Goldkorn, Simone Filosto, Samuel Chung, David S. Baston, Cathleen Becker |
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Rok vydání: | 2013 |
Předmět: |
Transcriptional Activation
Cancer Research Lung Neoplasms Cell Survival Antineoplastic Agents Biology medicine.disease_cause Proto-Oncogene Mas Article Carcinoma Non-Small-Cell Lung Cell Line Tumor medicine Humans Phosphorylation Receptor Protein Kinase Inhibitors A549 cell Mutation Smoking Phenotype respiratory tract diseases ErbB Receptors Gene Expression Regulation Neoplastic src-Family Kinases Oncology Drug Resistance Neoplasm Immunology Cancer research Erlotinib Tyrosine kinase Protein Binding medicine.drug Proto-oncogene tyrosine-protein kinase Src |
Zdroj: | Molecular Cancer Therapeutics. 12:1579-1590 |
ISSN: | 1538-8514 1535-7163 |
Popis: | The EGF receptor (EGFR) is a proto-oncogene commonly dysregulated in several cancers including non–small cell lung carcinoma (NSCLC) and, thus, is targeted for treatment using tyrosine kinase inhibitors (TKI) such as erlotinib. However, despite the efficacy observed in patients with NSCLC harboring oncogenic variants of the EGFR, general ineffectiveness of TKIs in patients with NSCLC who are current and former smokers necessitates identification of novel mechanisms to overcome this phenomenon. Previously, we showed that NSCLC cells harboring either wild-type (WT) EGFR or oncogenic mutant (MT) L858R EGFR become resistant to the effects of TKIs when exposed to cigarette smoke, evidenced by their autophosphorylation and prolonged downstream signaling. Here, we present Src as a target mediating cigarette smoke–induced resistance to TKIs in both WT EGFR- and L858R MT EGFR–expressing NSCLC cells. First, we show that cigarette smoke exposure of A549 cells leads to time-dependent activation of Src, which then abnormally binds to the WT EGFR causing TKI resistance, contrasting previous observations of constitutive binding between inactive Src and TKI-sensitive L858R MT EGFR. Next, we show that Src inhibition restores TKI sensitivity in cigarette smoke–exposed NSCLC cells, preventing EGFR autophosphorylation in the presence of erlotinib. Furthermore, we show that overexpression of a dominant-negative Src (Y527F/K295R) restores TKI sensitivity to A549 exposed to cigarette smoke. Importantly, the TKI resistance that emerges even in cigarette smoke–exposed L858R EGFR–expressing NSCLC cells could be eliminated with Src inhibition. Together, these findings offer new rationale for using Src inhibitors for treating TKI-resistant NSCLC commonly observed in smokers. Mol Cancer Ther; 12(8); 1579–90. ©2013 AACR. |
Databáze: | OpenAIRE |
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