Karoulia Zoi, Wu Yang, Ahmed Tamer A, Xin Qisheng, Bollard Julien, Krepler Clemens, Wu Xuewei, Zhang Chao, Bollag Gideon, Herlyn Meenhard, Fagin James A, Lujambio Amaia, Gavathiotis Evripidis, Poulikakos Poulikos I
Department of Oncological Sciences, Department of Dermatology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Department of Biochemistry, Department of Medicine, Albert Einstein Cancer Center, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Cancer Cell. 2016 Sep 12;30(3):485-498. doi: 10.1016/j.ccell.2016.06.024. Epub 2016 Aug 11.
The complex biochemical effects of RAF inhibitors account for both the effectiveness and mechanisms of resistance to these drugs, but a unified mechanistic model has been lacking. Here we show that RAF inhibitors exert their effects via two distinct allosteric mechanisms. Drug resistance due to dimerization is determined by the position of the αC helix stabilized by inhibitor, whereas inhibitor-induced RAF priming and dimerization are the result of inhibitor-induced formation of the RAF/RAS-GTP complex. The biochemical effect of RAF inhibitor in cells is the combined outcome of the two mechanisms. Therapeutic strategies including αC-helix-IN inhibitors are more effective in multiple mutant BRAF-driven tumor models, including colorectal and thyroid BRAF(V600E) cancers, in which first-generation RAF inhibitors have been ineffective.
RAF抑制剂复杂的生化效应解释了这些药物的有效性和耐药机制，但一直缺乏统一的机制模型。在此，我们表明RAF抑制剂通过两种不同的变构机制发挥作用。由二聚化导致的耐药性取决于抑制剂稳定的αC螺旋的位置，而抑制剂诱导的RAF引发和二聚化是抑制剂诱导形成RAF/RAS-GTP复合物的结果。RAF抑制剂在细胞中的生化效应是这两种机制共同作用的结果。包括αC螺旋-IN抑制剂在内的治疗策略在多种由突变BRAF驱动的肿瘤模型中更有效，这些模型包括结直肠癌和甲状腺BRAF（V600E）癌，而第一代RAF抑制剂在这些模型中无效。
