• Carminia Maria Della Corte, Claudio Bellevicine, Giovanni Vicidomini, Donata Vitagliano, Umberto Malapelle, Marina Accardo, Alessio Fabozzi, Alfonso Fiorelli, Morena Fasano, Federica Papaccio, Erika Martinelli, Teresa Troiani, Giancarlo Troncone, Mario Santini, Roberto Bianco, Fortunato Ciardiello, and Floriana Morgillo.
• Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Naples, Italy.
• Clin Cancer Res. 2015 Oct 15; 21 (20): 4686-97.

PurposeResistance to tyrosine kinase inhibitors (TKI) of EGF receptor (EGFR) is often related to activation of other signaling pathways and evolution through a mesenchymal phenotype.Experimental DesignBecause the Hedgehog (Hh) pathway has emerged as an important mediator of epithelial-to-mesenchymal transition (EMT), we studied the activation of Hh signaling in models of EGFR-TKIs intrinsic or acquired resistance from both EGFR-mutated and wild-type (WT) non-small cell lung cancer (NSCLC) cell lines.ResultsActivation of the Hh pathway was found in both models of EGFR-mutated and EGFR-WT NSCLC cell line resistant to EGFR-TKIs. In EGFR-mutated HCC827-GR cells, we found SMO (the Hh receptor) gene amplification, MET activation, and the functional interaction of these two signaling pathways. In HCC827-GR cells, inhibition of SMO or downregulation of GLI1 (the most important Hh-induced transcription factor) expression in combination with MET inhibition exerted significant antitumor activity.In EGFR-WT NSCLC cell lines resistant to EGFR inhibitors, the combined inhibition of SMO and EGFR exerted a strong antiproliferative activity with a complete inhibition of PI3K/Akt and MAPK phosphorylation. In addition, the inhibition of SMO by the use of LDE225 sensitizes EGFR-WT NSCLC cells to standard chemotherapy.ConclusionsThis result supports the role of the Hh pathway in mediating resistance to anti-EGFR-TKIs through the induction of EMT and suggests new opportunities to design new treatment strategies in lung cancer.©2015 American Association for Cancer Research.

55 keywords...

hide…