各种肿瘤中，感兴趣的In-frame BRAF exon 12 deletions逐渐增多。通常，BRAFΔβ3-αC致癌蛋白缺少β3-αC螺旋相关区的五个氨基酸，并且有时会发生新编插入。关于这些BRAFΔβ3-αC致癌蛋白的二聚化状态、其精确的发病机制以及它们对RAF抑制剂（RAFi）的直接可药性一直存在辩论。在这里，我们对BRAFΔLNVTAP>F和两种新的突变体BRAFdelinsFS和BRAFΔLNVT>F进行功能特性鉴定，并将它们与其他BRAFΔβ3-αC致癌蛋白进行比较。我们发现，BRAFΔβ3-αC致癌蛋白不仅可以形成稳定的同源二聚体和大型多蛋白复合体，而且需要二聚化。然而，细节很重要，因为一些BRAFΔβ3-αC致癌蛋白（例如BRAFΔLNVTAP>F）中缺失连接点的芳香族氨基酸不仅增加了它们的稳定性和二聚化倾向，而且还对偏向单体的RAFi（例如dabrafenib或HSP 90/CDC37抑制剂）产生了抗药性。相反，偏向二聚化的抑制剂（如naporafenib）可以在细胞系和患者源性器官样体中抑制所有的BRAFΔβ3-αC突变体，这表明由这些致癌蛋白驱动的肿瘤对这些化合物是脆弱的。

In-frame BRAF exon 12 deletions are increasingly identified in various tumor types. The resultant BRAFΔβ3-αC oncoproteins usually lack five amino acids in the β3-αC helix linker and sometimes contain de novo insertions. The dimerization status of BRAFΔβ3-αC oncoproteins, their precise pathomechanism, and their direct druggability by RAF inhibitors (RAFi) has been under debate. Here, we functionally characterize BRAFΔLNVTAP>F and two novel mutants, BRAFdelinsFS and BRAFΔLNVT>F, and compare them with other BRAFΔβ3-αC oncoproteins. We show that BRAFΔβ3-αC oncoproteins not only form stable homodimers and large multiprotein complexes but also require dimerization. Nevertheless, details matter as aromatic amino acids at the deletion junction of some BRAFΔβ3-αC oncoproteins, e.g., BRAFΔLNVTAP>F, increase their stability and dimerization propensity while conferring resistance to monomer-favoring RAFi such as dabrafenib or HSP 90/CDC37 inhibition. In contrast, dimer-favoring inhibitors such as naporafenib inhibit all BRAFΔβ3-αC mutants in cell lines and patient-derived organoids, suggesting that tumors driven by such oncoproteins are vulnerable to these compounds.