Therapeutic Discovery Cigarette Smoke Induces Aberrant EGF Receptor Activation That Mediates Lung Cancer Development and Resistance to Tyrosine Kinase Inhibitors
نویسندگان
چکیده
TheEGF receptor (EGFR) and its downstreamsignaling are implicated in lung cancer development. Therefore, much effort was spent in developing specific tyrosine kinase inhibitors (TKI) that bind to the EGFRATP-pocket, blocking EGFR phosphorylation/signaling. Clinical use of TKIs is effective in a subset of lung cancers with mutations in theEGFRkinasedomain, rendering the receptorhighly susceptible to TKIs.However, these benefits are limited, and emergence of additional EGFR mutations usually results in TKI resistance and disease progression. Previously, we showed one mechanism linking cigarette smoke to EGFR-driven lung cancer. Specifically, exposure of lung epithelial cells to cigarette smoke-induced oxidative stress stimulates aberrant EGFR phosphorylation/activation with impaired receptor ubiquitination/degradation. The abnormal stabilizationof theactivatedreceptor leads touncontrolledcell growthand tumorigenesis.Here,wedescribe for thefirst time a novel posttranslational mechanism of EGFR resistance to TKIs. Exposure of airway epithelial cells to cigarette smoke causesaberrantphosphorylation/activationofEGFR, resulting ina conformation that isdifferent from that induced by the ligand EGF. Unlike EGF-activated EGFR, cigarette smoke-activated EGFR binds c-Src and caveolin-1 anddoesnotundergo canonical dimerization. Importantly, the cigarette smoke-activatedEGFR is not inhibited by TKIs (AG1478; erlotinib; gefitinib); in fact, the cigarette smoke exposure induces TKI-resistance even in the TKI-sensitive EGFR mutants. Our findings show that cigarette smoke exposure stimulates not only aberrant EGFR phosphorylation impairing receptor degradation, but also induces a different EGFR conformation and signaling that are resistant to TKIs. Together, these findings offer new insights into cigarette smoke-induced lung cancer development and TKI resistance. Mol Cancer Ther; 11(4); 795–804. 2012 AACR.
منابع مشابه
Cigarette smoke induces aberrant EGF receptor activation that mediates lung cancer development and resistance to tyrosine kinase inhibitors.
The EGF receptor (EGFR) and its downstream signaling are implicated in lung cancer development. Therefore, much effort was spent in developing specific tyrosine kinase inhibitors (TKI) that bind to the EGFR ATP-pocket, blocking EGFR phosphorylation/signaling. Clinical use of TKIs is effective in a subset of lung cancers with mutations in the EGFR kinase domain, rendering the receptor highly sus...
متن کاملCigarette smoke induces aberrant EGF receptor activation which mediates lung cancer development and resistance to tyrosine kinase inhibitors
Abbreviations used are: ~, about; α, anti-; ∆, delta (deletion); Ab or Abs, antibody or antibodies; Cav-1, caveolin-1; CS, cigarette smoke; EDAC, 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; H2O2, hydrogen peroxide; HAE, human airway epithelial; HRP, horseradish peroxidase; IB, or IBed, immuno-blotting or imm...
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