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000282502 1001_ $$aLauinger, Manuel$$b0
000282502 245__ $$aBRAFΔβ3-αC in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability.
000282502 260__ $$aWashington, DC [u.a.]$$bAssoc.$$c2023
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000282502 520__ $$aIn-frame BRAF exon 12 deletions are increasingly identified in various tumor types. The resultant BRAFΔβ3-αC oncoproteins usually lack five amino acids in the β3-αC helix linker and sometimes contain de novo insertions. The dimerization status of BRAFΔβ3-αC oncoproteins, their precise pathomechanism, and their direct druggability by RAF inhibitors (RAFi) has been under debate. Here, we functionally characterize BRAFΔLNVTAP>F and two novel mutants, BRAFdelinsFS and BRAFΔLNVT>F, and compare them with other BRAFΔβ3-αC oncoproteins. We show that BRAFΔβ3-αC oncoproteins not only form stable homodimers and large multiprotein complexes but also require dimerization. Nevertheless, details matter as aromatic amino acids at the deletion junction of some BRAFΔβ3-αC oncoproteins, e.g., BRAFΔLNVTAP>F, increase their stability and dimerization propensity while conferring resistance to monomer-favoring RAFi such as dabrafenib or HSP 90/CDC37 inhibition. In contrast, dimer-favoring inhibitors such as naporafenib inhibit all BRAFΔβ3-αC mutants in cell lines and patient-derived organoids, suggesting that tumors driven by such oncoproteins are vulnerable to these compounds.
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000282502 7001_ $$0P:(DE-He78)1be4559cc9b0a41e8c03eaaeedc0cdde$$aChristen, Daniel$$b1
000282502 7001_ $$0P:(DE-He78)71295eda12004f9546701877c606ee82$$aKlar, Rhena$$b2
000282502 7001_ $$00000-0003-1658-8972$$aRoubaty, Carole$$b3
000282502 7001_ $$0P:(DE-He78)42b6114cd48e033299b2b6ef4bf56cc6$$aHeilig, Christoph$$b4
000282502 7001_ $$00000-0002-9443-9326$$aStumpe, Michael$$b5
000282502 7001_ $$aKnox, Jennifer J$$b6
000282502 7001_ $$00000-0002-8224-7263$$aRadulovich, Nikolina$$b7
000282502 7001_ $$aTamblyn, Laura$$b8
000282502 7001_ $$00000-0002-4911-1364$$aXie, Irene Y$$b9
000282502 7001_ $$0P:(DE-He78)5ea1944c122bc098a81df27a05572719$$aHorak, Peter$$b10
000282502 7001_ $$00000-0002-6185-4945$$aForschner, Andrea$$b11
000282502 7001_ $$00000-0002-4463-8263$$aBitzer, Michael$$b12
000282502 7001_ $$00000-0001-6194-2374$$aWittel, Uwe A$$b13
000282502 7001_ $$0P:(DE-He78)49bdb7cb4094fbf35c269ffa3e93ebc6$$aBörries, Melanie$$b14$$udkfz
000282502 7001_ $$0P:(DE-He78)7a10ea1b9b2872da9f375002c44ddfce$$aBall, Claudia$$b15
000282502 7001_ $$0P:(DE-He78)1464357f7ec5faf677a390a414e50c88$$aHeining, Christoph$$b16
000282502 7001_ $$0P:(DE-He78)157277fe62f07df1732f9d126a51d1b9$$aGlimm, Hanno$$b17
000282502 7001_ $$aFröhlich, Martina$$b18
000282502 7001_ $$0P:(DE-He78)a5218e4871866cd5ab2312e594ca403d$$aHübschmann, Daniel$$b19
000282502 7001_ $$aGallinger, Steven$$b20
000282502 7001_ $$aFritsch, Ralph$$b21
000282502 7001_ $$0P:(DE-He78)f0144d171d26dbedb67c9db1df35629d$$aFröhling, Stefan$$b22
000282502 7001_ $$00000-0002-8690-403X$$aO'Kane, Grainne M$$b23
000282502 7001_ $$00000-0002-9453-4614$$aDengjel, Jörn$$b24
000282502 7001_ $$0P:(DE-He78)492a2f9f2a95bcb0609e37d1ce1e13a9$$aBrummer, Tilman$$b25
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