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Combinatorial treatment using targeted MEK and SRC inhibitors synergistically abrogates tumor cell growth and induces mesenchymal-epithelial transition in non-small-cell lung carcinoma

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 PD0325...

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Autores principales: Chua, Kian Ngiap, Kong, Li Ren, Sim, Wen Jing, Ng, Hsien Chun, Ong, Weijie Richard, Thiery, Jean Paul, Huynh, Hung, Goh, Boon Cher
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745777/
https://www.ncbi.nlm.nih.gov/pubmed/26358373
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author Chua, Kian Ngiap
Kong, Li Ren
Sim, Wen Jing
Ng, Hsien Chun
Ong, Weijie Richard
Thiery, Jean Paul
Huynh, Hung
Goh, Boon Cher
author_facet Chua, Kian Ngiap
Kong, Li Ren
Sim, Wen Jing
Ng, Hsien Chun
Ong, Weijie Richard
Thiery, Jean Paul
Huynh, Hung
Goh, Boon Cher
author_sort Chua, Kian Ngiap
collection PubMed
description 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 (IC(50) < 2 μM) 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.
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spelling pubmed-47457772016-02-23 Combinatorial treatment using targeted MEK and SRC inhibitors synergistically abrogates tumor cell growth and induces mesenchymal-epithelial transition in non-small-cell lung carcinoma Chua, Kian Ngiap Kong, Li Ren Sim, Wen Jing Ng, Hsien Chun Ong, Weijie Richard Thiery, Jean Paul Huynh, Hung Goh, Boon Cher Oncotarget Research Paper 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 (IC(50) < 2 μM) 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. Impact Journals LLC 2015-08-17 /pmc/articles/PMC4745777/ /pubmed/26358373 Text en Copyright: © 2015 Chua et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Chua, Kian Ngiap
Kong, Li Ren
Sim, Wen Jing
Ng, Hsien Chun
Ong, Weijie Richard
Thiery, Jean Paul
Huynh, Hung
Goh, Boon Cher
Combinatorial treatment using targeted MEK and SRC inhibitors synergistically abrogates tumor cell growth and induces mesenchymal-epithelial transition in non-small-cell lung carcinoma
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
title_full Combinatorial treatment using targeted MEK and SRC inhibitors synergistically abrogates tumor cell growth and induces mesenchymal-epithelial transition in non-small-cell lung carcinoma
title_fullStr Combinatorial treatment using targeted MEK and SRC inhibitors synergistically abrogates tumor cell growth and induces mesenchymal-epithelial transition in non-small-cell lung carcinoma
title_full_unstemmed Combinatorial treatment using targeted MEK and SRC inhibitors synergistically abrogates tumor cell growth and induces mesenchymal-epithelial transition in non-small-cell lung carcinoma
title_short Combinatorial treatment using targeted MEK and SRC inhibitors synergistically abrogates tumor cell growth and induces mesenchymal-epithelial transition in non-small-cell lung carcinoma
title_sort combinatorial treatment using targeted mek and src inhibitors synergistically abrogates tumor cell growth and induces mesenchymal-epithelial transition in non-small-cell lung carcinoma
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745777/
https://www.ncbi.nlm.nih.gov/pubmed/26358373
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