PDF(Pubmed)
Abstract：
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 BRAF inhibitors (BRAFi) show high levels of target promiscuity, which can contribute to these effects. The blood vessel lining is in direct contact with high plasma concentrations of BRAFi, but effects of the inhibitors in this cell type are unknown. Hence, we aimed to characterize responses to approved BRAFi for melanoma in the vascular endothelium. We showed that clinically approved BRAFi induced a paradoxical activation of endothelial MAPK signaling. Moreover, phosphoproteomics revealed distinct sets of off-targets per inhibitor. Endothelial barrier function and junction integrity were impaired upon treatment with vemurafenib and the next-generation dimerization inhibitor PLX8394, but not with dabrafenib or encorafenib. Together, these findings provide insights into the surprisingly distinct side effects of BRAFi on endothelial signaling and functionality. Better understanding of off-target effects could help to identify molecular mechanisms behind AEs and guide the continued development of therapies for BRAF-mutant melanoma.
摘要：
针对突变型BRAF的靶向疗法有效地与MEK抑制剂(MEKi)组合使用以治疗晚期黑素瘤。然而,治疗成功受耐药和不良事件（AE）的影响。批准的BRAF抑制剂（BRAFi）显示高水平的目标滥交，这可能有助于这些影响。血管内膜与血浆中高浓度的BRAFi直接接触，但是抑制剂在这种细胞类型中的作用是未知的。因此，我们旨在表征血管内皮对已批准的BRAFi治疗黑色素瘤的反应。我们表明临床批准的BRAFi诱导内皮MAPK信号传导的矛盾激活。此外，磷酸蛋白质组学揭示了每种抑制剂不同的脱靶组。使用vemurafenib和下一代二聚化抑制剂PLX8394治疗后，内皮屏障功能和连接完整性受损，但使用dabrafenib或encorafenib治疗时未受损。一起,这些发现为了解BRAFi对内皮信号和功能的惊人的明显副作用提供了见解.更好地了解脱靶效应可以帮助确定AE背后的分子机制，并指导BRAF突变黑色素瘤的治疗方法的持续发展。
