O-mannosylation and protein maturation checkpoints represent therapeutic opportunities in BRAF fusion protein oncogenesis
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.
Authors
- Todd R. Golub (ORCID: https://orcid.org/0000-0003-0113-2403)
- Aaron Fultineer
- Eric S. Fischer (ORCID: https://orcid.org/0000-0001-7337-6306)
- Hiren J. Joshi (ORCID: https://orcid.org/0000-0002-8192-2829)
- Alexandra L. Condurat (ORCID: https://orcid.org/0000-0002-7297-3982)
- Sara C. Buch-Larsen (ORCID: https://orcid.org/0000-0001-6250-5467)
- Kevin N. Zhou (ORCID: https://orcid.org/0000-0003-1567-3606)
- Keith L. Ligon (ORCID: https://orcid.org/0000-0002-7733-600X)
- Jenna Robinson (ORCID: https://orcid.org/0000-0002-4062-0373)
- Sangita Pal (ORCID: https://orcid.org/0000-0002-4892-841X)
- Jesse S. Boehm (ORCID: https://orcid.org/0000-0002-6795-6336)
- Lorena Lazo de la Vega (ORCID: https://orcid.org/0000-0003-3609-0098)
- April A. Apfelbaum (ORCID: https://orcid.org/0000-0002-3551-4429)
- Louise Clark (ORCID: https://orcid.org/0000-0002-0574-5963)
- Tanaz Abid
- Sergey Y. Vakhrushev (ORCID: https://orcid.org/0000-0002-0418-5765)
- Mounica Vallurupalli (ORCID: https://orcid.org/0000-0002-1995-5283)
- Elizabeth M. Gonzalez (ORCID: https://orcid.org/0000-0001-6424-1522)
- Esteban Miglietta (ORCID: https://orcid.org/0000-0002-4898-7794)
- Enquan Xu (ORCID: https://orcid.org/0000-0003-3463-0337)
- Gianluca Lopez (ORCID: https://orcid.org/0000-0002-9262-1212)
- Till Milde (ORCID: https://orcid.org/0000-0002-7267-1052)
- Daniela Kocher (ORCID: https://orcid.org/0009-0007-0235-1081)
- Tanaz Sharifnia (ORCID: https://orcid.org/0000-0001-7274-164X)
- Beth A. Cimini (ORCID: https://orcid.org/0000-0001-9640-9318)
- Merve Özdemir (ORCID: https://orcid.org/0009-0009-6825-6305)
- Daniel P. Bondeson (ORCID: https://orcid.org/0000-0001-9564-8149)
- Tilman Brummer (ORCID: https://orcid.org/0000-0003-4387-7905)
- Michael J. Eck (ORCID: https://orcid.org/0000-0003-4247-9403)
- Rameen Beroukhim (ORCID: https://orcid.org/0000-0001-6303-3609)
- Jason J. Kwon (ORCID: https://orcid.org/0000-0002-3053-2919)
- Jesper Velgaard Olsen (ORCID: https://orcid.org/0000-0002-4747-4938)
- Frederik De Smet (ORCID: https://orcid.org/0000-0002-6669-3335)
- Adnan Halim (ORCID: https://orcid.org/0000-0003-1629-187X)
- Seth Malinowski (ORCID: https://orcid.org/0000-0001-6468-3451)
- Ivo A. Hendriks (ORCID: https://orcid.org/0000-0002-1439-3701)
- Nicole S. Persky (ORCID: https://orcid.org/0000-0002-9948-2761)
- Anne E. Carpenter (ORCID: https://orcid.org/0000-0003-1555-8261)
- Carolina Ortiz‐Cordero (ORCID: https://orcid.org/0000-0001-6953-0366)
- Sean A. Misek (ORCID: https://orcid.org/0000-0002-0246-5018)
- Katherine A. Janeway (ORCID: https://orcid.org/0000-0001-6000-3594)
- Henrik Clausen (ORCID: https://orcid.org/0000-0002-0915-5055)
- Corina Anastasaki (ORCID: https://orcid.org/0000-0002-9928-6488)
- Amy Goodale (ORCID: https://orcid.org/0000-0003-4294-5777)
- Jörn Dengjel (ORCID: https://orcid.org/0000-0002-9453-4614)
- Ke Xia Cai
- Anna Borgenvik (ORCID: https://orcid.org/0000-0003-4696-7703)
- William C. Hahn (ORCID: https://orcid.org/0000-0003-2840-9791)
- David H. Gutmann (ORCID: https://orcid.org/0000-0002-3127-5045)
- Timothy N. Phoenix (ORCID: https://orcid.org/0000-0003-4771-4003)
- Hyesung Jeon (ORCID: https://orcid.org/0000-0002-0034-5469)
- Nada Jabado (ORCID: https://orcid.org/0000-0003-2485-3692)
- Michael Stumpe (ORCID: https://orcid.org/0000-0002-9443-9326)
- Dana Novikov (ORCID: https://orcid.org/0000-0002-1388-9270)
- Zohra Kalani (ORCID: https://orcid.org/0000-0003-2707-8097)
- Sandra Jacobs (ORCID: https://orcid.org/0000-0002-9455-5394)
- Brittany C. Parker Kerrigan (ORCID: https://orcid.org/0009-0005-9268-0342)
- Pratiti Bandopadhayay (ORCID: https://orcid.org/0000-0002-4175-4760)
- David E. Root (ORCID: https://orcid.org/0000-0001-5122-861X)
- Lobna A. Elsadek
- Romain Sigaud (ORCID: https://orcid.org/0000-0002-8600-8876)
- Timothy Ragnoni
- Hongyu Li (ORCID: https://orcid.org/0000-0001-6525-9310)
- David Jones (ORCID: https://orcid.org/0000-0002-2036-5141)
- Sarah Reel (ORCID: https://orcid.org/0000-0003-1025-6707)
- Sher Bahadur
- Anna Kovarzin
- Antonio Maldera
- Kira Tang
- Daniel Christen
- Michelle Boisvert
- Jacquelyn Jones (ORCID: https://orcid.org/0009-0001-3762-0444)
- Gloria Kyrila
- Joohee Lee
- Alexander Zhang (ORCID: https://orcid.org/0009-0002-7459-7607)
- Noah Schulman (ORCID: https://orcid.org/0009-0003-3844-5945)
- Julie Parikh (ORCID: https://orcid.org/0009-0007-9742-2312)
- Seung Hyun Choi (ORCID: https://orcid.org/0009-0008-6685-9324)
- Zachary Eisenbies (ORCID: https://orcid.org/0009-0006-5320-0040)
Institutions
- Broad Institute (US)
- University of Copenhagen (DK)
- Cincinnati Children's Hospital Medical Center (US)
- Harvard University (US)
- University of Fribourg (CH)
- University of Freiburg (DE)
- German Cancer Research Center (DE)
- Washington University in St. Louis (US)
- Heidelberg University (DE)
- University Medical Center Freiburg (DE)
- Somerville Hospital (US)
- University Hospital Heidelberg (DE)
- Yale University (US)
- Breakthrough (US)
- Hopp Children's Cancer Center Heidelberg (DE)
- Dana-Farber Cancer Institute (US)
- Yale New Haven Health System (US)
- University of Education Freiburg (DE)
- Jena University Hospital (DE)
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center (US)
- McGill University (CA)
- University of Cincinnati (US)
- Massachusetts Institute of Technology (US)
- IT University of Copenhagen (DK)
- KU Leuven (BE)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2026-09-09
- DOI
- https://doi.org/10.1158/2159-8290.cd-25-1114
- Primary Topic
- Microtubule and mitosis dynamics
- Type
- article
- Field-Weighted Citation Impact
- 0.00