Journal Article

DKFZ-2026-02234

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png O-mannosylation and protein maturation checkpoints represent therapeutic opportunities in BRAF fusion protein oncogenesis.

Borgenvik, A. ; Misek, S. A. ; Christen, D.DKFZ* ; Kyrila, G. ; Zhang, A. ; Reel, S. ; Boisvert, M. ; Cai, K. Y. ; Kovarzin, A. ; Li, H. ; Zhou, K. N. ; Gonzalez, E. M. ; Buch-Larsen, S. C. ; Hendriks, I. A. ; Olsen, J. V. ; Anastasaki, C. ; Xu, E. ; Goodale, A. ; Lazo de la Vega, L. ; Ragnoni, T. J. ; Kalani, Z. ; Persky, N. S. ; Abid, T. ; Miglietta, E. A. ; Vakhrushev, S. Y. ; Stumpe, M. ; Jones, J. S. ; Malinowski, S. ; Elsadek, L. A. ; Parikh, J. ; Condurat, A. L. ; Fultineer, A. ; Choi, S. H. ; Ozdemir, M. ; Eisenbies, Z. ; Lee, J. ; Novikov, D. ; Bahadur, S. ; Apfelbaum, A. A. ; Robinson, J. ; Clark, L. M. ; Schulman, N. ; Lopez, G. ; Kocher, D. ; Ortiz-Cordero, C. ; Tang, K. ; Maldera, A. ; Bondeson, D. P. ; Kwon, J. J. ; Vallurupalli, M. ; Jeon, H. ; Pal, S. ; Jacobs, S. ; Golub, T. R. ; Hahn, W. C. ; De Smet, F. ; Sigaud, R. ; Fischer, E. S. ; Boehm, J. S. ; Dengjel, J. ; Clausen, H. ; Jabado, N. ; Milde, T. ; Carpenter, A. E. ; Gutmann, D. H. ; Cimini, B. A. ; Ligon, K. L. ; Janeway, K. A. ; Eck, M. J. ; Parker Kerrigan, B. C. ; Root, D. E. ; Jones, D.DKFZ* ; Sharifnia, T. ; Phoenix, T. N. ; Beroukhim, R. ; Joshi, H. J. ; Brummer, T. ; Halim, A. ; Bandopadhayay, P.

2026
[Verlag nicht ermittelbar] Philadelphia, Pa.

Abstract: Fusions between protein-coding genes are common oncogenic drivers, typically pairing a proto-oncogene with a partner that does not independently drive cancer. In all therapeutically actionable fusions, the proto-oncogene is the drug target, the contributions to oncogenicity of the fusion partner have largely been ignored. We studied the role of BRAF fusion partners and found that they are necessary for transformation. In the setting of KIAA1549::BRAF, the most common fusion protein across brain tumors, we found that KIAA1549 is necessary for oncogenicity of KIAA1549::BRAF and engenders a striking and specific dependency on the protein O-mannosyltransferase complex (POMT1/2). Specifically, we show that genetic silencing or pharmacologic inhibition of POMT1/2 reverses fusion-induced transformation, thereby representing a novel and MAPK-independent therapeutic target. Furthermore, POMT1/2 is required to glycosylate and enable maturation of the K::B fusion protein. These findings represent a proof-of-concept for targeting the partners in oncogenic fusions as a potential cancer therapeutic strategy.

Note: epub

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Contributing Institute(s):

1. Pädiatrische Gliomforschung (B360)

Research Program(s):

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

Appears in the scientific report 2026

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Essential Science Indicators ; IF >= 25 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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