Abstract B019: O-mannosylation represents a therapeutic opportunity in BRAF fusion protein oncogenesis

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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Journal
Cancer Research
Published
2025-09-25
DOI
https://doi.org/10.1158/1538-7445.pediatric25-b019
Primary Topic
Cancer Research and Treatments
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article
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article

Abstract B019: O-mannosylation represents a therapeutic opportunity in BRAF fusion protein oncogenesis

Todd R. Golub, Daniel Christen, Eric S. Fischer, Hiren J. Joshi et al.
Cancer Research
Cancer Research and Treatments
article

Abstract B019: O-mannosylation represents a therapeutic opportunity in BRAF fusion protein oncogenesis

Todd R. Golub, Daniel Christen, Eric S. Fischer, Hiren J. Joshi, Kathrine Janeway, Kevin N. Zhou, Keith Lloyd Ligon, Jenna Robinson, Sangita Pal, Jesse S. Boehm, Lorena Lazo de la Vega, April A. Apfelbaum, Mounica Vallurupalli, Esteban Miglietta, Till Milde, Beth A. Cimini, Merve Özdemir, Daniel P. Bondeson, Tilman Brummer, Michael J. Eck, Jason J. Kwon, Adnan Halim, Seth Malinowski, Joo-Hee Lee, Sean A. Misek, Amy Goodale, Jörn Dengjel, Ke Xia Cai, Anna Borgenvik, William C. Hahn, Timothy N. Phoenix, Alexander Zhang, Nada Jabado, Rameen Beroukhim, Michelle Boisvert, Pratiti Bandopadhayay, David E. Root, Lobna A. Elsadek, David Jones, Jacquelyn Jones, Elizabeth Gonzáles, Henrik F. Clausen, Zachary Eisenbies, Antonio Maldera, Gloria Kyrila, Sarah Reel
article en

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.

Cancer ResearchVol. 85(18_Supplement_2)
Broad Institute (US), University of Copenhagen (DK), Cincinnati Children's Hospital Medical Center (US), University of Fribourg (CH), University of Freiburg (DE), University College Copenhagen (DK), Hopp Children's Cancer Center Heidelberg (DE), Dana-Farber Cancer Institute (US), University of Education Freiburg (DE), Jena University Hospital (DE), McGill University (CA), University of Cincinnati (US), IT University of Copenhagen (DK), University of Cincinnati Medical Center (US)
Openalex Percentile: Top 72%
Cancer Research and Treatments
DOISourceOpenAlex
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