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.
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 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.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Kian Ngiap
authors.initials: KN
authors.lastname: Chua
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Li Ren
authors.initials: LR
authors.lastname: Kong
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR, Singapore.
authors.forename: Wen Jing
authors.initials: WJ
authors.lastname: Sim
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR, Singapore.
authors.forename: Hsien Chun
authors.initials: HC
authors.lastname: Ng
authors.affiliation: National Cancer Centre, Singapore.
authors.forename: Weijie Richard
authors.initials: WR
authors.lastname: Ong
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Institute of Molecular and Cell Biology, A*STAR, Singapore.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Thiery
authors.affiliation: National Cancer Centre, Singapore.
authors.forename: Hung
authors.initials: H
authors.lastname: Huynh
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Department of Hematology-Oncology, National University Hospital, Singapore.|National University Cancer Institute, Singapore.
authors.forename: Boon Cher
authors.initials: BC
authors.lastname: Goh
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology; D015820:Cadherins / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018613:Microscopy, Confocal; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001549:Benzamides; D052117:Benzodioxoles; D015820:Cadherins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C506614:mirdametinib; C515233:saracatinib; D004159:Diphenylamine; D019061:src-Family Kinases; D048369:MAP Kinase Kinase 1
keywords: MEK and SRC inhibitor combination treatment; PD0325901; mesenchymal-epithelial transition inducer; non-small-cell lung cancer; saracatinib