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| 024 | 7 | _ | |a 10.1158/1535-7163.MCT-19-1021 |2 doi |
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| 024 | 7 | _ | |a 1535-7163 |2 ISSN |
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| 037 | _ | _ | |a DKFZ-2020-01284 |
| 041 | _ | _ | |a eng |
| 082 | _ | _ | |a 570 |
| 100 | 1 | _ | |a Usta, Diren |0 P:(DE-He78)7d5cd95cbedad26188a1df9eeca335ef |b 0 |e First author |u dkfz |
| 245 | _ | _ | |a A cell-based MAPK reporter assay reveals synergistic MAPK pathway activity suppression by MAPK inhibitor combination in BRAF-driven pediatric low-grade glioma cells. |
| 260 | _ | _ | |a Philadelphia, Pa. |c 2020 |b AACR |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1600169247_28878 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
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| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 500 | _ | _ | |a 2020 Aug;19(8):1736-1750#EA:B310#LA:B310# |
| 520 | _ | _ | |a Pilocytic 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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| 700 | 1 | _ | |a Buhl, Juliane L |0 P:(DE-HGF)0 |b 2 |
| 700 | 1 | _ | |a Selt, Florian |0 P:(DE-He78)a23e88cc676489fe05be8c178ceaf58e |b 3 |u dkfz |
| 700 | 1 | _ | |a Marquardt, Viktoria |0 P:(DE-He78)da540cf439735fb1385a3a90933baa23 |b 4 |
| 700 | 1 | _ | |a Pauck, David |0 P:(DE-He78)964e19ad88fd6ff751ae2c10599ad7cc |b 5 |u dkfz |
| 700 | 1 | _ | |a Jansen, Jennifer |b 6 |
| 700 | 1 | _ | |a Pusch, Stefan |0 P:(DE-He78)f2efee17b6ca2f790176a2c036912536 |b 7 |u dkfz |
| 700 | 1 | _ | |a Ecker, Jonas |0 P:(DE-He78)3de637452ba900e2bdd359b8f41953bf |b 8 |u dkfz |
| 700 | 1 | _ | |a Hielscher, Thomas |0 P:(DE-He78)743a4a82daab55306a2c88b9f6bf8c2f |b 9 |u dkfz |
| 700 | 1 | _ | |a Vollmer, Johanna |0 P:(DE-He78)8e8f606a151be408d2e21ce3e1f3822f |b 10 |u dkfz |
| 700 | 1 | _ | |a Sommerkamp, Alexander C |0 P:(DE-He78)193d882d3418c5d0ffbb210947510711 |b 11 |u dkfz |
| 700 | 1 | _ | |a Rubner, Tobias |0 P:(DE-He78)c6630b8b192d9388bbf45e5166946b76 |b 12 |u dkfz |
| 700 | 1 | _ | |a Hargrave, Darren |0 0000-0001-8219-9807 |b 13 |
| 700 | 1 | _ | |a van Tilburg, Cornelis Martinus |0 P:(DE-He78)a6b5fcabf661bef95109dbee87dc5271 |b 14 |u dkfz |
| 700 | 1 | _ | |a Pfister, Stefan M |0 P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9 |b 15 |u dkfz |
| 700 | 1 | _ | |a Jones, David T W |0 P:(DE-He78)551bb92841f634070997aa168d818492 |b 16 |u dkfz |
| 700 | 1 | _ | |a Remke, Marc |0 P:(DE-He78)a244aa021112b9002419791434bbc71c |b 17 |u dkfz |
| 700 | 1 | _ | |a Brummer, Tilman |b 18 |
| 700 | 1 | _ | |a Witt, Olaf |0 P:(DE-He78)143af26de9d57bf624771616318aaf7c |b 19 |u dkfz |
| 700 | 1 | _ | |a Milde, Till |0 P:(DE-He78)0be2f86573954f87e97f8a4dbb05cb0f |b 20 |e Last author |u dkfz |
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