ArticleMolecular cancer therapeutics2013
Src mediates cigarette smoke-induced resistance to tyrosine kinase inhibitors in NSCLC cells.
Article in Molecular cancer therapeutics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
19 citing papers in PubMed, 1 synthesis or guideline pooled it, 34 citations in OpenAlex.
- Pooled it
- Influence of Smoking Habits on the Efficacy of EGFR-TKI Therapy in Patients with Advanced NSCLC: A Systematic Review and Meta-Analysis.Clinical Medicine Insights. Oncology · 2023Article
- Design, synthesis and biological evaluation of a series of dianilinopyrimidines as EGFR inhibitors.Journal of enzyme inhibition and medicinal chemistry · 2022Article
- BMSC-derived leptin and IGFBP2 promote erlotinib resistance in lung adenocarcinoma cells through IGF-1R activation in hypoxic environment.Cancer biology & therapy · 2020Article
- Prognostic Significance of Cigarette Smoking in Association with Histologic Subtypes of Resected Lung Adenocarcinoma.The Korean journal of thoracic and cardiovascular surgery · 2019Article
- Cumulative smoking dose affects the clinical outcomes of EGFR-mutated lung adenocarcinoma patients treated with EGFR-TKIs: a retrospective study.BMC cancer · 2018Article
- High cripto-1 and low miR-205 expression levels as prognostic markers in early stage non-small cell lung cancer.Lung cancer (Amsterdam, Netherlands) · 2018Article
- Targeting focal adhesion kinase overcomes erlotinib resistance in smoke induced lung cancer by altering phosphorylation of epidermal growth factor receptor.Oncoscience · 2018Article
- Impact of active smoking on survival of patients with metastatic lung adenocarcinoma harboring an epidermal growth factor receptor (EGFR) mutation.Bosnian journal of basic medical sciences · 2016Article
- Article
- Omics for prediction of environmental health effects: Blood leukocyte-based cross-omic profiling reliably predicts diseases associated with tobacco smoking.Scientific reports · 2016Article
- Intrinsic resistance to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer with activating EGFR mutations.OncoTargets and therapy · 2016Review
- Reversine Induced Multinucleated Cells, Cell Apoptosis and Autophagy in Human Non-Small Cell Lung Cancer Cells.PloS one · 2016Article
- EGF-receptor specificity for phosphotyrosine-primed substrates provides signal integration with Src.Nature structural & molecular biology · 2015Article
- Src regulates cigarette smoke-induced ceramide generation via neutral sphingomyelinase 2 in the airway epithelium.American journal of respiratory cell and molecular biology · 2015Article
- Cigarette smoking impairs the response of EGFR-TKIs therapy in lung adenocarcinoma patients by promoting EGFR signaling and epithelial-mesenchymal transition.American journal of translational research · 2015Article
- Lung injury and lung cancer caused by cigarette smoke-induced oxidative stress: Molecular mechanisms and therapeutic opportunities involving the ceramide-generating machinery and epidermal growth factor receptor.Antioxidants & redox signaling · 2014Review
- The biological and clinical effects of smoking by patients with cancer and strategies to implement evidence-based tobacco cessation support.The Lancet. Oncology · 2014Review
- Molecular mechanisms of resistance in epidermal growth factor receptor-mutant lung adenocarcinomas.European respiratory review : an official journal of the European Respiratory Society · 2014Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
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.
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Registered trials
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