MEK inhibition induces apoptosis in osteosarcoma cells with constitutive ERK1/2 phosphorylation.

TitleMEK inhibition induces apoptosis in osteosarcoma cells with constitutive ERK1/2 phosphorylation.
Publication TypeJournal Article
Year of Publication2015
AuthorsBaranski, Z., Booij T.H., Kuijjer M.L., de Jong Y., Cleton-Jansen A.-M., Price L.S., van de Water B., Bovée J.V.M.G., Hogendoorn P.C.W., Danen E.H.J.
JournalGenes Cancer
Volume6
Pagination503-12
Date Published2015 Nov
ISSN1947-6019
Abstract

Conventional high-grade osteosarcoma is the most common primary bone cancer with relatively high incidence in young people. Recurrent and metastatic tumors are difficult to treat. We performed a kinase inhibitor screen in two osteosarcoma cell lines, which identified MEK1/2 inhibitors. These inhibitors were further validated in a panel of six osteosarcoma cell lines. Western blot analysis was performed to assess ERK activity and efficacy of MEK inhibition. A 3D culture system was used to validate results from 2D monolayer cultures. Gene expression analysis was performed to identify differentially expressed gene signatures in sensitive and resistant cell lines. Activation of the AKT signaling network was explored using Western blot and pharmacological inhibition. In the screen, Trametinib, AZD8330 and TAK-733 decreased cell viability by more than 50%. Validation in six osteosarcoma cell lines identified three cell lines as resistant and three as sensitive to the inhibitors. Western blot analysis of ERK activity revealed that sensitive lines had high constitutive ERK activity. Treatment with the three MEK inhibitors in a 3D culture system validated efficacy in inhibition of osteosarcoma viability. MEK1/2 inhibition represents a candidate treatment strategy for osteosarcomas displaying high MEK activity as determined by ERK phosphorylation status.

DOI10.18632/genesandcancer.91
Alternate JournalGenes Cancer
PubMed ID26807203
10/05/2016