title: 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.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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
  Activation 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.
  
  
  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.
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Carminia Maria
authors.initials: CM
authors.lastname: Della Corte
authors.affiliation: Dipartimento di Sanità Pubblica, Università degli Studi di Napoli Federico II, Naples, Italy. Università degli Studi di Napoli Federico II, Naples, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Bellevicine
authors.affiliation: Chirurgia Toracica, Dipartimento di Scienze Cardio-Toraciche e Respiratorie, Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Vicidomini
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Donata
authors.initials: D
authors.lastname: Vitagliano
authors.affiliation: Dipartimento di Sanità Pubblica, Università degli Studi di Napoli Federico II, Naples, Italy. Università degli Studi di Napoli Federico II, Naples, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Malapelle
authors.affiliation: Anatomia Patologica, Dipartimento di Salute Mentale e Fisica e Medicina Preventiva, Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Accardo
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Fabozzi
authors.affiliation: Chirurgia Toracica, Dipartimento di Scienze Cardio-Toraciche e Respiratorie, Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Fiorelli
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Morena
authors.initials: M
authors.lastname: Fasano
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Papaccio
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Martinelli
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Troiani
authors.affiliation: Dipartimento di Sanità Pubblica, Università degli Studi di Napoli Federico II, Naples, Italy. Università degli Studi di Napoli Federico II, Naples, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Troncone
authors.affiliation: Chirurgia Toracica, Dipartimento di Scienze Cardio-Toraciche e Respiratorie, Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Santini
authors.affiliation: Oncologia Medica, Dipartimento di Medicina clinica e Chirurgia, Università degli Studi di Napoli Federico II, Naples, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bianco
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Naples, Italy. florianamorgillo@yahoo.com.
authors.forename: Floriana
authors.initials: F
authors.lastname: Morgillo
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D005784:Gene Amplification / Q000187:drug effects / Q000235:genetics*; D053823:Hedgehog Proteins / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000072086:Smoothened Receptor
chemical_list: D001713:Biphenyl Compounds; D066246:ErbB Receptors; D053823:Hedgehog Proteins; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; D000072086:Smoothened Receptor; C491023:SMO protein, human; C561435:sonidegib; C512478:EGFR protein, human