Please use this identifier to cite or link to this item: https://doi.org/10.18632/oncotarget.5031
Title: Combinatorial treatment using targeted MEK and SRC inhibitors synergistically abrogates tumor cell growth and induces mesenchymal-epithelial transition in non-small-cell lung carcinoma
Authors: Chua, K.N 
Kong, L.R 
Sim, W.J 
Ng, H.C
Ong, W.R
Thiery, J.P 
Huynh, H 
Goh, B.C 
Keywords: focal adhesion kinase
n (2,3 dihydroxypropoxy) 3,4 difluoro 2 (2 fluoro 4 iodoanilino)benzamide
paxillin
plakoglobin
saracatinib
transcription factor Snail
uvomorulin
1,3 benzodioxole derivative
benzamide derivative
cadherin
diphenylamine
mitogen activated protein kinase kinase 1
n (2,3 dihydroxypropoxy) 3,4 difluoro 2 (2 fluoro 4 iodoanilino)benzamide
protein kinase inhibitor
protein tyrosine kinase
quinazoline derivative
saracatinib
anchorage independent growth
animal cell
animal experiment
animal model
animal tissue
Article
cancer control
cancer growth
cancer inhibition
carcinogenicity
cell invasion
cell migration
cell proliferation
controlled study
drug potentiation
epithelial mesenchymal transition
female
G1 phase cell cycle checkpoint
lung cancer cell line
mouse
non small cell lung cancer
nonhuman
protein expression
protein localization
tumor xenograft
analogs and derivatives
animal
antagonists and inhibitors
Bagg albino mouse
Carcinoma, Non-Small-Cell Lung
cell adhesion
cell cycle
cell motion
confocal microscopy
dose response
drug effects
drug potentiation
drug screening
enzymology
epithelial mesenchymal transition
human
immunoblotting
Lung Neoplasms
metabolism
nude mouse
pathology
tumor volume
Animals
Benzamides
Benzodioxoles
Cadherins
Carcinoma, Non-Small-Cell Lung
Cell Adhesion
Cell Cycle
Cell Movement
Cell Proliferation
Diphenylamine
Dose-Response Relationship, Drug
Drug Synergism
Epithelial-Mesenchymal Transition
Female
Humans
Immunoblotting
Lung Neoplasms
MAP Kinase Kinase 1
Mice, Inbred BALB C
Mice, Nude
Microscopy, Confocal
Protein Kinase Inhibitors
Quinazolines
src-Family Kinases
Tumor Burden
Xenograft Model Antitumor Assays
Issue Date: 2015
Citation: Chua, K.N, Kong, L.R, Sim, W.J, Ng, H.C, Ong, W.R, Thiery, J.P, Huynh, H, Goh, B.C (2015). Combinatorial treatment using targeted MEK and SRC inhibitors synergistically abrogates tumor cell growth and induces mesenchymal-epithelial transition in non-small-cell lung carcinoma. Oncotarget 6 (30) : 29991-30005. ScholarBank@NUS Repository. https://doi.org/10.18632/oncotarget.5031
Abstract: Oncogenesis in non-small cell lung cancer (NSCLC) is regulated by a complex signal transduction network. Single-agent targeted therapy fails frequently due to treatment insensitivity and acquired resistance. In this study, we demonstrate that co-inhibition of the MAPK and SRC pathways using a PD0325901 and Saracatinib kinase inhibitor combination can abrogate tumor growth in NSCLC. PD0325901/Saracatinib at 0.25:1 combination was screened against a panel of 28 NSCLC cell lines and 68% of cell lines were found to be sensitive (IC50 < 2 ?M) to this combination. In Snail1 positive NSCLC lines, the drug combination complementarily enhanced mesenchymal-epithelial transition (MET), increasing both E-cadherin and Plakoglobin expression, and reducing Snail1, FAK and PXN expression. In addition, the drug combination abrogated cell migration and matrigel invasion. The co-inhibition of MAPK and SRC induced strong G1/G0 cell cycle arrest in the NSCLC lines, inhibited anchorage independent growth and delayed tumor growth in H460 and H358 mouse xenografts. These data provide rationale for further investigating the combination of MAPK and SRC pathway inhibitors in advanced stage NSCLC.
Source Title: Oncotarget
URI: https://scholarbank.nus.edu.sg/handle/10635/174135
ISSN: 19492553
DOI: 10.18632/oncotarget.5031
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