Journal Article

DKFZ-2023-01791

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png BRAFΔβ3-αC in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability.

Lauinger, M. ; Christen, D.DKFZ* ; Klar, R.DKFZ* ; Roubaty, C. ; Heilig, C.DKFZ* ; Stumpe, M. ; Knox, J. J. ; Radulovich, N. ; Tamblyn, L. ; Xie, I. Y. ; Horak, P.DKFZ* ; Forschner, A.DKFZ* ; Bitzer, M.DKFZ* ; Wittel, U. A. ; Börries, M.DKFZ* ; Ball, C.DKFZ* ; Heining, C.DKFZ* ; Glimm, H.DKFZ* ; Fröhlich, M. ; Hübschmann, D.DKFZ* ; Gallinger, S. ; Fritsch, R. ; Fröhling, S.DKFZ* ; O'Kane, G. M. ; Dengjel, J. ; Brummer, T.DKFZ*

2023
Assoc. Washington, DC [u.a.]

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Please use a persistent id in citations: doi:10.1126/sciadv.ade7486

Abstract: 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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Contributing Institute(s):

1. DKTK Koordinierungsstelle Freiburg (FR01)
2. Translationale Medizinische Onkologie (B340)
3. DKTK HD zentral (HD01)
4. DKTK Koordinierungsstelle Tübingen (TU01)
5. DKTK Koordinierungsstelle Dresden (DD01)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2023

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