MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling

Abstract

The epidermal growth factor receptor (EGFR) kinase inhibitors gefitinib and erlotinib are effective treatments for lung cancers with EGFR activating mutations, but these tumors invariably develop drug resistance. Here, we describe a gefitinib-sensitive lung cancer cell line that developed resistance to gefitinib as a result of focal amplification of the MET proto-oncogene. inhibition of MET signaling in these cells restored their sensitivity to gefitinib. MET amplification was detected in 4 of 18 (22%) lung cancer specimens that had developed resistance to gefitinib or erlotinib. We find that amplification of MET causes gefitinib resistance by driving ERBB3 (HER3)–dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors. Thus, we propose that MET amplification may promote drug resistance in other ERBB-driven cancers as well.

Keywords

GefitinibErlotinibERBB3Epidermal growth factor receptorLung cancerCancer researchErbBERBB4Drug resistanceOncogeneMedicineBiologyCancerOncologyReceptorInternal medicineReceptor tyrosine kinaseCell cycleGenetics

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Publication Info

Year: 2007
Type: article
Volume: 316
Issue: 5827
Pages: 1039-1043
Citations: 4399
Access: Closed

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APA Style

                            
                                
                                    Jeffrey A. Engelman, 
                                
                                    Kreshnik Zejnullahu, 
                                
                                    Tetsuya Mitsudomi
                                
                                et al.
                            
                            (2007). 
                            <i>MET</i> Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling. 
                            Science
                            , 316
                            (5827)
                            , 1039-1043.
                            https://doi.org/10.1126/science.1141478
                        

Identifiers

DOI: 10.1126/science.1141478