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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 |
Appears in Collections: | Elements Staff Publications |
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