Off-targets of BRAF inhibitors disrupt endothelial signaling and vascular barrier function

• DOI: 10.26508/lsa.202402671
• Publication Date: 2024-06-05T16:45:22Z
• Authors: Sophie Bromberger; Yuliia Zadorozhna; Julia Maria Ressler; Silvio Holzner; Arkadiusz Nawrocki; Nina Zila; Alexander Springer; Martin Røssel Larsen; Klaudia Schosslei...
• Keywords: Dabrafenib; Trametinib; V600E

Targeted therapies against mutant BRAF are effectively used in combination with MEK inhibitors (MEKi) to treat advanced melanoma. However, treatment success is affected by resistance and adverse events (AEs). Approved (BRAFi) show high levels of target promiscuity, which can contribute these effects. The blood vessel lining direct contact plasma concentrations BRAFi, but effects the this cell type unknown. Hence, we aimed characterize responses approved BRAFi for melanoma vascular endothelium. We showed that clinically induced a paradoxical activation endothelial MAPK signaling. Moreover, phosphoproteomics revealed distinct sets off-targets per inhibitor. Endothelial barrier function junction integrity were impaired upon vemurafenib next-generation dimerization inhibitor PLX8394, not dabrafenib or encorafenib. Together, findings provide insights into surprisingly side on signaling functionality. Better understanding off-target could help identify molecular mechanisms behind AEs guide continued development BRAF-mutant