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.

Gefitinib inhibits invasive phenotype and epithelial-mesenchymal transition in drug-resistant NSCLC cells with MET amplification / LA MONICA, Silvia; Caffarra, Cristina; Saccani, Francesca; Galvani, Elena; Galetti, Maricla; Fumarola, Claudia; Bonelli, Mara; Cavazzoni, Andrea; D., Cretella; R., Sirangelo; Gatti, Rita; Tiseo, Marcello; Ardizzoni, Andrea; E., Giovannetti; Petronini, Pier Giorgio; Alfieri, Roberta. - In: PLOS ONE. - ISSN 1932-6203. - 8:(2013), p. e78656. [10.1371/journal.pone.0078656]

Gefitinib inhibits invasive phenotype and epithelial-mesenchymal transition in drug-resistant NSCLC cells with MET amplification

LA MONICA, Silvia;CAFFARRA, Cristina;SACCANI, Francesca;GALVANI, Elena;GALETTI, Maricla;FUMAROLA, Claudia;BONELLI, Mara;CAVAZZONI, Andrea;GATTI, Rita;TISEO, Marcello;ARDIZZONI, Andrea;PETRONINI, Pier Giorgio;ALFIERI, Roberta
2013-01-01

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.
2013
Gefitinib inhibits invasive phenotype and epithelial-mesenchymal transition in drug-resistant NSCLC cells with MET amplification / LA MONICA, Silvia; Caffarra, Cristina; Saccani, Francesca; Galvani, Elena; Galetti, Maricla; Fumarola, Claudia; Bonelli, Mara; Cavazzoni, Andrea; D., Cretella; R., Sirangelo; Gatti, Rita; Tiseo, Marcello; Ardizzoni, Andrea; E., Giovannetti; Petronini, Pier Giorgio; Alfieri, Roberta. - In: PLOS ONE. - ISSN 1932-6203. - 8:(2013), p. e78656. [10.1371/journal.pone.0078656]
File in questo prodotto:
File Dimensione Formato  
PLOS ONE 2013.pdf

non disponibili

Tipologia: Documento in Post-print
Licenza: Creative commons
Dimensione 1.98 MB
Formato Adobe PDF
1.98 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2651268
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 39
  • ???jsp.display-item.citation.isi??? 37
social impact