title: Gefitinib inhibits invasive phenotype and epithelial-mesenchymal transition in drug-resistant NSCLC cells with MET amplification.
abstract: Despite the initial response, all patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). The EGFR-T790M secondary mutation is responsible for half of acquired resistance cases, while MET amplification has been associated with acquired resistance in about 5-15% of NSCLCs. Clinical findings indicate the retained addiction of resistant tumors on EGFR signaling. Therefore, we evaluated the molecular mechanisms supporting the therapeutic potential of gefitinib maintenance in the HCC827 GR5 NSCLC cell line harbouring MET amplification as acquired resistance mechanism. We demonstrated that resistant cells can proliferate and survive regardless of the presence of gefitinib, whereas the absence of the drug significantly enhanced cell migration and invasion. Moreover, the continuous exposure to gefitinib prevented the epithelial-mesenchymal transition (EMT) with increased E-cadherin expression and down-regulation of vimentin and N-cadherin. Importantly, the inhibition of cellular migration was correlated with the suppression of EGFR-dependent Src, STAT5 and p38 signaling as assessed by a specific kinase array, western blot analysis and silencing functional studies. On the contrary, the lack of effect of gefitinib on EGFR phosphorylation in the H1975 cells (EGFR-T790M) correlated with the absence of effects on cell migration and invasion. In conclusion, our findings suggest that certain EGFR-mutated patients may still benefit from a second-line therapy including gefitinib based on the specific mechanism underlying tumor cell resistance.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: La Monica
authors.forename: Cristina
authors.initials: C
authors.lastname: Caffarra
authors.forename: Francesca
authors.initials: F
authors.lastname: Saccani
authors.forename: Elena
authors.initials: E
authors.lastname: Galvani
authors.forename: Maricla
authors.initials: M
authors.lastname: Galetti
authors.forename: Claudia
authors.initials: C
authors.lastname: Fumarola
authors.forename: Mara
authors.initials: M
authors.lastname: Bonelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavazzoni
authors.forename: Daniele
authors.initials: D
authors.lastname: Cretella
authors.forename: Rita
authors.initials: R
authors.lastname: Sirangelo
authors.forename: Rita
authors.initials: R
authors.lastname: Gatti
authors.forename: Marcello
authors.initials: M
authors.lastname: Tiseo
authors.forename: Andrea
authors.initials: A
authors.lastname: Ardizzoni
authors.forename: Elisa
authors.initials: E
authors.lastname: Giovannetti
authors.forename: Pier Giorgio
authors.initials: PG
authors.lastname: Petronini
authors.forename: Roberta R
authors.initials: RR
authors.lastname: Alfieri
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D000077156:Gefitinib; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D000077156:Gefitinib