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