PMID- 26124204
OWN - NLM
STAT- MEDLINE
DCOM- 20160801
LR  - 20220321
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Linking)
VI  - 21
IP  - 20
DP  - 2015 Oct 15
TI  - 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.
PG  - 4686-97
LID - 10.1158/1078-0432.CCR-14-3319 [doi]
AB  - 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: 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.
CI  - (c)2015 American Association for Cancer Research.
FAU - Della Corte, Carminia Maria
AU  - Della Corte CM
AD  - Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e 
      Sperimentale "F. Magrassi e A. Lanzara," Seconda Universita degli Studi di 
      Napoli, Naples, Italy.
FAU - Bellevicine, Claudio
AU  - Bellevicine C
AD  - Dipartimento di Sanita Pubblica, Universita degli Studi di Napoli Federico II, 
      Naples, Italy. Universita degli Studi di Napoli Federico II, Naples, Italy.
FAU - Vicidomini, Giovanni
AU  - Vicidomini G
AD  - Chirurgia Toracica, Dipartimento di Scienze Cardio-Toraciche e Respiratorie, 
      Seconda Universita degli Studi di Napoli, Naples, Italy.
FAU - Vitagliano, Donata
AU  - Vitagliano D
AD  - Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e 
      Sperimentale "F. Magrassi e A. Lanzara," Seconda Universita degli Studi di 
      Napoli, Naples, Italy.
FAU - Malapelle, Umberto
AU  - Malapelle U
AD  - Dipartimento di Sanita Pubblica, Universita degli Studi di Napoli Federico II, 
      Naples, Italy. Universita degli Studi di Napoli Federico II, Naples, Italy.
FAU - Accardo, Marina
AU  - Accardo M
AD  - Anatomia Patologica, Dipartimento di Salute Mentale e Fisica e Medicina 
      Preventiva, Seconda Universita degli Studi di Napoli, Naples, Italy.
FAU - Fabozzi, Alessio
AU  - Fabozzi A
AD  - Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e 
      Sperimentale "F. Magrassi e A. Lanzara," Seconda Universita degli Studi di 
      Napoli, Naples, Italy.
FAU - Fiorelli, Alfonso
AU  - Fiorelli A
AD  - Chirurgia Toracica, Dipartimento di Scienze Cardio-Toraciche e Respiratorie, 
      Seconda Universita degli Studi di Napoli, Naples, Italy.
FAU - Fasano, Morena
AU  - Fasano M
AD  - Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e 
      Sperimentale "F. Magrassi e A. Lanzara," Seconda Universita degli Studi di 
      Napoli, Naples, Italy.
FAU - Papaccio, Federica
AU  - Papaccio F
AD  - Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e 
      Sperimentale "F. Magrassi e A. Lanzara," Seconda Universita degli Studi di 
      Napoli, Naples, Italy.
FAU - Martinelli, Erika
AU  - Martinelli E
AD  - Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e 
      Sperimentale "F. Magrassi e A. Lanzara," Seconda Universita degli Studi di 
      Napoli, Naples, Italy.
FAU - Troiani, Teresa
AU  - Troiani T
AD  - Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e 
      Sperimentale "F. Magrassi e A. Lanzara," Seconda Universita degli Studi di 
      Napoli, Naples, Italy.
FAU - Troncone, Giancarlo
AU  - Troncone G
AD  - Dipartimento di Sanita Pubblica, Universita degli Studi di Napoli Federico II, 
      Naples, Italy. Universita degli Studi di Napoli Federico II, Naples, Italy.
FAU - Santini, Mario
AU  - Santini M
AD  - Chirurgia Toracica, Dipartimento di Scienze Cardio-Toraciche e Respiratorie, 
      Seconda Universita degli Studi di Napoli, Naples, Italy.
FAU - Bianco, Roberto
AU  - Bianco R
AD  - Oncologia Medica, Dipartimento di Medicina clinica e Chirurgia, Universita degli 
      Studi di Napoli Federico II, Naples, Italy.
FAU - Ciardiello, Fortunato
AU  - Ciardiello F
AD  - Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e 
      Sperimentale "F. Magrassi e A. Lanzara," Seconda Universita degli Studi di 
      Napoli, Naples, Italy.
FAU - Morgillo, Floriana
AU  - Morgillo F
AD  - Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e 
      Sperimentale "F. Magrassi e A. Lanzara," Seconda Universita degli Studi di 
      Napoli, Naples, Italy. florianamorgillo@yahoo.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150629
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Biphenyl Compounds)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyridines)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 0 (SMO protein, human)
RN  - 0 (Smoothened Receptor)
RN  - 0RLU3VTK5M (sonidegib)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Animals
MH  - Biphenyl Compounds/pharmacology
MH  - Carcinoma, Non-Small-Cell Lung/drug therapy/genetics
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects/genetics
MH  - Down-Regulation/drug effects/genetics
MH  - Drug Resistance, Neoplasm/drug effects/*genetics
MH  - Epithelial-Mesenchymal Transition/drug effects/genetics
MH  - ErbB Receptors/*antagonists & inhibitors
MH  - Female
MH  - Gene Amplification/drug effects/*genetics
MH  - Hedgehog Proteins/*genetics
MH  - Humans
MH  - Lung Neoplasms/drug therapy/*genetics
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Phosphatidylinositol 3-Kinases/genetics
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Proto-Oncogene Proteins c-akt/genetics
MH  - Proto-Oncogene Proteins c-met/genetics
MH  - Pyridines/pharmacology
MH  - Receptors, G-Protein-Coupled/antagonists & inhibitors/*genetics
MH  - Signal Transduction/drug effects/genetics
MH  - Smoothened Receptor
EDAT- 2015/07/01 06:00
MHDA- 2016/08/02 06:00
CRDT- 2015/07/01 06:00
PHST- 2014/12/29 00:00 [received]
PHST- 2015/06/13 00:00 [accepted]
PHST- 2015/07/01 06:00 [entrez]
PHST- 2015/07/01 06:00 [pubmed]
PHST- 2016/08/02 06:00 [medline]
AID - 1078-0432.CCR-14-3319 [pii]
AID - 10.1158/1078-0432.CCR-14-3319 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2015 Oct 15;21(20):4686-97. doi: 10.1158/1078-0432.CCR-14-3319. 
      Epub 2015 Jun 29.