Purpose: Resistance 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 Design: Because 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. Results: Activationof theHh pathwaywas found inbothmodels of EGFR-mutated and EGFR-WT NSCLC cell line resistant to EGFRTKIs. 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 ofSMOor downregulation ofGLI1 (themost 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. Conclusions:This 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.
SMO Gene Amplification and Activation of the Hedgehog Pathway as Novel Mechanisms of Resistance to Anti-Epidermal Growth Factor Receptor Drugs in Human Lung Cancer / Della Corte, Carminia Maria; Bellevicine, Claudio; Vicidomini, Giovanni; Vitagliano, Donata; Malapelle, Umberto; Accardo, Marina; Fabozzi, Alessio; Fiorelli, Alfonso; Fasano, Morena; Papaccio, Federica; Martinelli, Erika; Troiani, Teresa; Troncone, Giancarlo; Santini, Mario; Bianco, Roberto; Ciardiello, Fortunato; Morgillo, Floriana. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - 21:20(2015), pp. 4686-97-4697. [10.1158/1078-0432.CCR-14-3319]
SMO Gene Amplification and Activation of the Hedgehog Pathway as Novel Mechanisms of Resistance to Anti-Epidermal Growth Factor Receptor Drugs in Human Lung Cancer
BELLEVICINE, CLAUDIO;VITAGLIANO, DONATA;MALAPELLE, UMBERTO;TROIANI, TERESA;TRONCONE, GIANCARLO;BIANCO, ROBERTO;
2015
Abstract
Purpose: Resistance 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 Design: Because 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. Results: Activationof theHh pathwaywas found inbothmodels of EGFR-mutated and EGFR-WT NSCLC cell line resistant to EGFRTKIs. 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 ofSMOor downregulation ofGLI1 (themost 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. Conclusions:This 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.File | Dimensione | Formato | |
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