Targeting BRAF kinase fusions with pan-RAF and vertical MAPK inhibition
Turner, J. A.; MacBeth, M. L.; Bagby, S. M.; Whitty, P.; Hartman, S. J.; Simmons, D.; Pitts, T. M.; Yacob, B.; Robinson, W. A.; Couts, K.
Show abstract
BRAF kinase fusions are a form of structural variation in the genome and are recurrent events in driver-negative melanomas. While BRAF fusions reproducibly conserve the kinase domain, there is genetic variability with 5 gene partners and specific BRAF breakpoints. We investigated how genetic diversity of BRAF kinase fusions affects dimeric signaling and ERK activation. We overexpressed BRAF fusions with 5 gene partners including AGK, ZKSCAN1, ARMC10, PPFIBP2, and TRIM24 and found fusion dependent signaling and inhibitor sensitivity. Despite the development of next generation RAF inhibitors, there was paradoxical ERK phosphorylation with multiple pan-RAF inhibitors, which was ameliorated in certain BRAF fusions with vertical RAF/MEK inhibition using trametinib and LY3009120. Collectively, we observed some fusion-dependent effects but also tumor growth suppression and resolution of paradoxical activation with vertical pathway inhibition.
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