Abstract 7033: Unraveling <i>Kiaa1549</i>-<i>Braf</i> driven brain tumors: From modeling to therapy

Abstract The KIAA1549-BRAF (KB) fusion is a prevalent genetic event in two distinct central nervous system tumors: pilocytic astrocytomas (PAs) and diffuse leptomeningeal glioneuronal tumors (DLGNTs). This chromosomal rearrangement, consisting of a 2 Mbp tandem duplication at 7q34, results in the formation of a fusion protein absent in normal cells. The KB fusion protein has been described to dimerize the BRAF kinase in a RAS-independent manner, leading to a constitutive activation of the MAPK pathway and promoting tumorigenesis. Despite its significance, the lack of pre-clinical models limits our understanding of how KB promotes DLGNTs and PAs development, so effective therapeutic strategies remain elusive. To address this, we aimed to model the KB fusion at its endogenous chromosomal location. Overcoming the challenges of modeling chromosomal rearrangements, we used the CRISPR-Cas9 gene-editing technique to model the fusion event ex vivo and in vivo in the mouse brain, leveraging p53- or Arf-deleted backgrounds. These models allow us to investigate the molecular mechanisms by which KB promotes tumor initiation and progression and test the therapeutic potential of Belvarafenib, a class II BRAF inhibitor that targets BRAF dimers. Our results demonstrate that CRISPR-mediated engineering of KB in p53- or Arf-deficient backgrounds, both ex vivo and in vivo, generates CNS tumors resembling human DLGNTs in their histology and growth patterns. Furthermore, targeting the robust MAPK pathway activation in these KB-driven tumor models with Belvarafenib significantly reduced ERK phosphorylation and tumor growth, and significantly increased the survival of treated mice. These findings demonstrate that KB promotes tumor initiation and progression, and highlight the therapeutic potential of Belvarafenib targeting this oncogenic event. Thus, our KB-DLGNTs model emerges as a valuable tool to evaluate the efficacy of novel pre-clinical BRAF inhibitors. Citation Format: Ylenia Cendon Florez, Ram Kannan, Matthias A. Karrajannis, Darlene Dela Cruz, Udi Segal, Danilo Maddalo, Scott Foster, Robert Benezra, Andrea Ventura. Unraveling Kiaa1549-Braf driven brain tumors: From modeling to therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7033.