O-Mannosylation as a novel therapeutic target for KIAA1549::BRAF-rearranged pediatric gliomas

Over 75% of pediatric low-grade gliomas (pLGGs) are driven by a single fusion between BRAF and the poorly characterized protein KIAA1549. Oddly, though KIAA1549 is the most common BRAF fusion partner, whether it plays a role in the fusion is unknown. MAPK pathway inhibitors are being used to target BRAF activation and have shown early promise in clinical trials.

Unfortunately, however, they are not curative. Strategies that result in sustained tumor responses are desperately needed.

We have conducted a genome-scale CRISPR/Cas9 screen and identified the two core members of the POMT complex (POMT1 and POMT2) as genes essential for survival of KIAA1549::BRAF-mutant models of pLGG. I have validated these findings in independent isogenic human neural stem cell models.

The POMT complex is vital for O-mannosylation of extracellular and transmembrane proteins, which is striking because KIAA1549 is among the most heavily mannosylated human proteins.

Excitingly, small molecule inhibitors of the yeast POMT complex have been developed, highlighting the tractability of POMT as a therapeutic target. My findings suggest that the KIAA1549 portion of the fusion is essential for oncogenic signaling.

Over the next 36 months I will investigate the hypothesis that O-mannosylation of KIAA1549::BRAF by the POMT complex is necessary for it’s oncogenicity. My work will be done at the Dana-Farber Cancer Institute, mentored by Dr. Bandopadhayay and Dr. Nelander at Uppsala University.