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000156979 1001_ $$0P:(DE-He78)7d5cd95cbedad26188a1df9eeca335ef$$aUsta, Diren$$b0$$eFirst author$$udkfz
000156979 245__ $$aA cell-based MAPK reporter assay reveals synergistic MAPK pathway activity suppression by MAPK inhibitor combination in BRAF-driven pediatric low-grade glioma cells.
000156979 260__ $$aPhiladelphia, Pa.$$bAACR$$c2020
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000156979 500__ $$a2020 Aug;19(8):1736-1750#EA:B310#LA:B310#
000156979 520__ $$aPilocytic astrocytomas (PAs) as well as other pediatric low-grade gliomas (pLGGs) exhibit genetic events leading to aberrant activation of the MAPK pathway. The most common alterations are KIAA1549:BRAF fusions, BRAFV600E and NF1 mutations. Novel drugs targeting the MAPK pathway (MAPKi) are prime candidates for the treatment of these single-pathway diseases. We aimed to develop an assay suitable for pre-clinical testing of MAPKi in pLGGs with the goal to identify novel MAPK pathway suppressing synergistic drug combinations. A reporter plasmid (pDIPZ) with a MAPK-responsive ELK-1-binding element driving the expression of destabilized firefly luciferase was generated and packaged using a lentiviral vector system. Pediatric glioma cell lines with a BRAF fusion (DKFZ-BT66) and a BRAFV600E mutation (BT-40) background, respectively, were stably transfected. Modulation of the MAPK pathway activity by MAPKi was measured using the luciferase reporter and validated by detection of phosphorylated protein levels. A screen of a MAPKi library was performed and synergy of selected combinations was calculated. Screening of a MAPKi library revealed MEK inhibitors as the class inhibiting the pathway with the lowest IC50s, followed by ERK and next-generation RAF inhibitors. Combination treatments with different MAPKi classes showed synergistic effects in BRAF fusion as well as BRAFV600E mutation backgrounds. We here report a novel reporter assay for medium- to high-throughput pre-clinical drug testing in pLGG cell lines. The assay confirmed MEK, ERK and next-generation RAF inhibitors as potential treatment approaches for KIAA1549:BRAF and BRAFV600E mutated pLGGs. In addition, the assay revealed that combination treatments synergistically suppressed MAPK pathway activity.
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000156979 7001_ $$0P:(DE-He78)a5e60710c7515b3e1de74ced6928a9dd$$aSigaud, Romain$$b1$$udkfz
000156979 7001_ $$0P:(DE-HGF)0$$aBuhl, Juliane L$$b2
000156979 7001_ $$0P:(DE-He78)a23e88cc676489fe05be8c178ceaf58e$$aSelt, Florian$$b3$$udkfz
000156979 7001_ $$0P:(DE-He78)da540cf439735fb1385a3a90933baa23$$aMarquardt, Viktoria$$b4
000156979 7001_ $$0P:(DE-He78)964e19ad88fd6ff751ae2c10599ad7cc$$aPauck, David$$b5$$udkfz
000156979 7001_ $$aJansen, Jennifer$$b6
000156979 7001_ $$0P:(DE-He78)f2efee17b6ca2f790176a2c036912536$$aPusch, Stefan$$b7$$udkfz
000156979 7001_ $$0P:(DE-He78)3de637452ba900e2bdd359b8f41953bf$$aEcker, Jonas$$b8$$udkfz
000156979 7001_ $$0P:(DE-He78)743a4a82daab55306a2c88b9f6bf8c2f$$aHielscher, Thomas$$b9$$udkfz
000156979 7001_ $$0P:(DE-He78)8e8f606a151be408d2e21ce3e1f3822f$$aVollmer, Johanna$$b10$$udkfz
000156979 7001_ $$0P:(DE-He78)193d882d3418c5d0ffbb210947510711$$aSommerkamp, Alexander C$$b11$$udkfz
000156979 7001_ $$0P:(DE-He78)c6630b8b192d9388bbf45e5166946b76$$aRubner, Tobias$$b12$$udkfz
000156979 7001_ $$00000-0001-8219-9807$$aHargrave, Darren$$b13
000156979 7001_ $$0P:(DE-He78)a6b5fcabf661bef95109dbee87dc5271$$avan Tilburg, Cornelis Martinus$$b14$$udkfz
000156979 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan M$$b15$$udkfz
000156979 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David T W$$b16$$udkfz
000156979 7001_ $$0P:(DE-He78)a244aa021112b9002419791434bbc71c$$aRemke, Marc$$b17$$udkfz
000156979 7001_ $$aBrummer, Tilman$$b18
000156979 7001_ $$0P:(DE-He78)143af26de9d57bf624771616318aaf7c$$aWitt, Olaf$$b19$$udkfz
000156979 7001_ $$0P:(DE-He78)0be2f86573954f87e97f8a4dbb05cb0f$$aMilde, Till$$b20$$eLast author$$udkfz
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