Abstract B019: O-mannosylation represents a therapeutic opportunity in BRAF fusion protein oncogenesis
Bibliographic record
Abstract
Abstract Fusions between protein-coding genes are common oncogenic drivers across cancers, 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. KIAA1549::BRAF (K::B) is the most common fusion protein across brain tumors, and particularly in pediatric gliomas. We found that KIAA1549 is necessary for oncogenicity of K::B, in contrast to the notion that the BRAF kinase domain alone is enough for transformation. We therefore performed genome-wide CRISPR/Cas9 anti-transformation screens in isogenic neural stem cell models with K::B overexpression to identify genetic dependencies specific to this oncogenic driver. We found that the BRAF fusion partner KIAA1549 engenders a striking and specific dependency on the protein O-mannosyltransferase complex (POMT1/2). Specifically, we show that genetic silencing or pharmacologic inhibition of the POMT1/2 complex reverses K::B transformation, thereby representing a novel therapeutic target beyond the MAPK pathway. Furthermore, POMT1/2 is required to glycosylate and enable maturation of K::B, reflecting the native biology of KIAA1549 but representing a non-canonical process for BRAF. These findings represent a proof-of-concept for targeting the partners in oncogenic fusions as a potential cancer therapeutic strategy. Citation Format: Anna Borgenvik, Sean Misek, Daniel Christen, Gloria Kyrila, Alexander Zhang, Sarah Reel, Michelle Boisvert, Kelly Cai, Kevin Zhou, Elizabeth M Gonzales, Lorena Lazo de la Vega, Amy Goodale, Esteban Miglietta, Jacquelyn Jones, Seth Malinowski, Lobna Elsadek, Merve Ozdemir, Zachary Eisenbies, Joohee Lee, April Apfelbaum, Jenna Robinson, Antonio Maldera, Daniel Bondeson, Jason Kwon, Mounica Vallurupalli, Sangita Pal, Todd Golub, William Hahn, Eric Fischer, Jesse Boehm, Jörn Dengjel, Henrik Clausen, Nada Jabado, Till Milde, Beth A Cimini, Keith Ligon, Kathrine Janeway, Michael Eck, David Root, David Jones, Timothy N Phoenix, Rameen Beroukhim, Hiren Jitendra Joshi, Tilman Brummer, Adnan Halim, Pratiti Bandopadhayay. O-mannosylation represents a therapeutic opportunity in BRAF fusion protein oncogenesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2):Abstract nr B019.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".