Exploiting Allosteric Properties of RAF and MEK Inhibitors to Target Therapy-Resistant Tumors Driven by Oncogenic BRAF Signaling.
Exploiting Allosteric Properties of RAF and MEK Inhibitors to Target Therapy-Resistant Tumors Driven by Oncogenic BRAF Signaling.
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DOI：
10.1158/2159-8290.cd-20-1351
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发表时间：
2021-07
期刊：
影响因子：
28.2
通讯作者：
Poulikakos PI
中科院分区：
文献类型：
--
作者：
Adamopoulos C;Ahmed TA;Tucker MR;Ung PMU;Xiao M;Karoulia Z;Amabile A;Wu X;Aaronson SA;Ang C;Rebecca VW;Brown BD;Schlessinger A;Herlyn M;Wang Q;Shaw DE;Poulikakos PI
目前的临床RAF抑制剂(RAF)抑制单体BRAF(MBRAF)，但对二聚体BRAF(DBRAF)的效力较弱。用于mBRAF和dBRAF的RAFI等效物已经开发出来，但预计治疗指数较低。这里，我们识别了第三类RAFI，它选择性地抑制dBRAF而不是mBRAF。分子动力学模拟表明，BRAFαC-螺旋的运动受到限制，这是抑制剂选择性的基础。基于构象选择性的抑制剂组合(mBRAF加dBRAF选择性加上最有效的BRAF-MEK干扰物MEK抑制剂)在BRAF(V600E)治疗耐药模型中促进了对肿瘤生长的抑制。引人注目的是，三联疗法没有显示出毒性，而dBRAF选择性加MEK抑制剂治疗导致小鼠体重减轻。最后，三联疗法在IV期结直肠癌患者中实现了持久的反应并改善了临床幸福感。因此，开发RAF和MEK抑制剂的变构特性使设计有效和耐受性良好的BRAF(V600E)肿瘤治疗成为可能。
Current clinical RAF inhibitors (RAFi) inhibit monomeric BRAF (mBRAF), but are less potent against dimeric BRAF (dBRAF). RAFi equipotent for mBRAF and dBRAF have been developed, but are predicted to have lower therapeutic index. Here we identify a third class of RAFi that selectively inhibits dBRAF over mBRAF. Molecular Dynamic simulations reveal restriction of the movement of the BRAF αC-helix as the basis of inhibitor selectivity. Combination of inhibitors based on their conformation selectivity (mBRAF- plus dBRAF-selective plus the most potent BRAF-MEK disruptor MEK inhibitor) promoted suppression of tumor growth in BRAF(V600E) therapy-resistant models. Strikingly, the triple combination showed no toxicities, whereas dBRAF-selective plus MEK inhibitor treatment caused weight loss in mice. Finally, the triple combination achieved durable response and improved clinical wellbeing in a stage IV colorectal cancer patient. Thus, exploiting allosteric properties of RAF and MEK inhibitors enables the design of effective and well-tolerated therapies for BRAF(V600E) tumors.