Pediatric brain tumors are the most frequent cause of cancer related death and morbidity in childhood. Of these, pediatric low-grade gliomas are the most frequent group of solid tumors of childhood, and most frequently harbor activating rearrangements involving BRAF. The oncogenicity of these fusions has been thought to arise from activation of MAPK-signaling from the unopposed BRAF kinase, resulting from loss of its N-terminal negative regulatory domain. Accordingly. therapeutic approaches for these gliomas has been directed towards inhibiting the downstream MAPK-activation. However, while these approaches have been associated with promising clinical responses, these responses are unfortunately not sustained in the majority of children, with gliomas exhibiting frequent regrowth on cessation of treatment, necessitating prolonged treatment. This is of particular concern as the long-term sequelae of long-term MAPK-pathway inhibition is completely unknown on normal development. Therapeutic targets beyond the MAPK pathway are required.
To address this, we performed a series of genome-scale CRISPR-cas9 scnrees across isogenic neural stem cell models transduced to express all of the recurrent drivers found in pediatric low-grade gliomas. Strikingly, we found KIAA1549-BRAF expressing cells to harbor a specific dependency on an enzyme complex that is predicted to act on KIAA1549, BRAF's fusion partner. This finding validated across orthogonal approaches, and isogenic model systems treated with a tool inhibitor exhibited specific sensitivity in the context of KIAA1549-BRAF expression. Combination approaches reveal synergy between the tool compound and clinically-relevant MAPK-pathway inhibitors. Importantly, we find KIAA1549 to be necessary for KIAA1549-BRAF induced transformation.
Our findings reveal, for the first time, the role of KIAA1549 in facilitating KIAA1549-BRAF mediated gliomagenesis, and reveal a novel and potentially druggable target outside the MAPK-pathway. Together, these observations open a completely unexplored research direction and therapeutic potential for the most common fusion protein in pediatric brain tumors.