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| Home > Publications database > BRAFΔβ3-αC in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability. > print |
| 001 | 282502 | ||
| 005 | 20240312125704.0 | ||
| 024 | 7 | _ | |a 10.1126/sciadv.ade7486 |2 doi |
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| 041 | _ | _ | |a English |
| 082 | _ | _ | |a 500 |
| 100 | 1 | _ | |a Lauinger, Manuel |b 0 |
| 245 | _ | _ | |a BRAFΔβ3-αC in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability. |
| 260 | _ | _ | |a Washington, DC [u.a.] |c 2023 |b Assoc. |
| 336 | 7 | _ | |a article |2 DRIVER |
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| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 520 | _ | _ | |a In-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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| 700 | 1 | _ | |a Roubaty, Carole |0 0000-0003-1658-8972 |b 3 |
| 700 | 1 | _ | |a Heilig, Christoph |0 P:(DE-He78)42b6114cd48e033299b2b6ef4bf56cc6 |b 4 |
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| 700 | 1 | _ | |a Knox, Jennifer J |b 6 |
| 700 | 1 | _ | |a Radulovich, Nikolina |0 0000-0002-8224-7263 |b 7 |
| 700 | 1 | _ | |a Tamblyn, Laura |b 8 |
| 700 | 1 | _ | |a Xie, Irene Y |0 0000-0002-4911-1364 |b 9 |
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| 700 | 1 | _ | |a Bitzer, Michael |0 0000-0002-4463-8263 |b 12 |
| 700 | 1 | _ | |a Wittel, Uwe A |0 0000-0001-6194-2374 |b 13 |
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| 700 | 1 | _ | |a Glimm, Hanno |0 P:(DE-He78)157277fe62f07df1732f9d126a51d1b9 |b 17 |
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| 773 | _ | _ | |a 10.1126/sciadv.ade7486 |g Vol. 9, no. 35, p. eade7486 |0 PERI:(DE-600)2810933-8 |n 35 |p eade7486 |t Science advances |v 9 |y 2023 |x 2375-2548 |
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