Cancer discovery · 2026

O-mannosylation and protein maturation checkpoints represent therapeutic opportunities in BRAF fusion protein oncogenesis.

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Borgenvik Anna, Misek Sean A, Christen Daniel, Kyrila Gloria, Zhang Alexander, Reel Sarah, Boisvert Michelle, Cai Kelly Y, Kovarzin Anna, Li Hongyu, Zhou Kevin N, Gonzalez Elizabeth M, Buch-Larsen Sara C, Hendriks Ivo A, Olsen Jesper V, Anastasaki Corina, Xu Enquan, Goodale Amy, Lazo de la Vega Lorena, Ragnoni Timothy J, Kalani Zohra, Persky Nicole S, Abid Tanaz, Miglietta Esteban A, Vakhrushev Sergey Y, Stumpe Michael, Jones Jacquelyn S, Malinowski Seth, Elsadek Lobna A, Parikh Julie, Condurat Alexandra L, Fultineer Aaron, Choi Seung Hyun, Ozdemir Merve, Eisenbies Zachary, Lee Joohee, Novikov Dana, Bahadur Sher, Apfelbaum April A, Robinson Jenna, Clark Louise M, Schulman Noah, Lopez Gianluca, Kocher Daniela, Ortiz-Cordero Carolina, Tang Kira, Maldera Antonio, Bondeson Daniel P, Kwon Jason J, Vallurupalli Mounica, Jeon Hyesung, Pal Sangita, Jacobs Sandra, Golub Todd R, Hahn William C, De Smet Frederik, Sigaud Romain, Fischer Eric S, Boehm Jesse S, Dengjel Jörn, Clausen Henrik, Jabado Nada, Milde Till, Carpenter Anne E, Gutmann David H, Cimini Beth A, Ligon Keith L, Janeway Katherine A, Eck Michael J, Parker Kerrigan Brittany C, Root David E, Jones David T W, Sharifnia Tanaz, Phoenix Timothy N, Beroukhim Rameen, Joshi Hiren J, Brummer Tilman, Halim Adnan, Bandopadhayay Pratiti

Аннотация

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.

O-mannosylation and protein maturation checkpoints represent therapeutic opportunities in BRAF fusion protein oncogenesis.

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Аннотация