文章：

靶向RAF激酶治疗人类癌症的新视角

New perspectives for targeting RAF kinase in human cancer

原文发布日期：2017-10-06

DOI: 10.1038/nrc.2017.79

类型: Review Article

开放获取: 否

要点：

1. The oncoprotein BRAF is frequently activated due to genetic alterations in tumours promoting deregulation of RAF–MEK–ERK signalling. Targeting BRAF with inhibitors is a validated therapeutic strategy for a substantial proportion of cancer patients.
2. RAF inhibitors alone or in combination with MEK inhibitors have elicited dramatic responses and prolonged the survival of patients with melanoma whose tumours harbour mutationally activated BRAF-V600. However, their effectiveness is limited by the development of drug resistance, frequently by mechanisms that promote reactivation of RAF–ERK signalling in the presence of the drug.
3. In BRAF-V600 tumours other than melanoma, or in tumours carrying BRAF alterations other than the BRAF-V600 mutation, current clinical RAF inhibitors have shown modest effectiveness.
4. RAF inhibitors have unique biochemical properties that account for their wide therapeutic window, on-target toxicities and major mechanisms of resistance.
5. RAF dimerization is a common mechanism of both intrinsic and acquired resistance to current clinical RAF inhibitors vemurafenib and dabrafenib, which stabilize the αC-helix of RAF kinase in the OUT position. These compounds effectively inhibit monomeric mutant BRAF but fail to inhibit dimeric RAF.
6. Structurally, inhibitor resistance due to RAF dimerization is the result of negative allostery for inhibitor binding to the second protomer of the RAF dimer, once the first is bound to an inhibitor.
7. Next-generation RAF inhibitors that stabilize the αC-helix of RAF kinase in the active (IN) position will inhibit RAF monomers and dimers, but they are predicted to have a narrow therapeutic window due to inhibition of wild-type BRAF in normal cells. Thus, combinatorial approaches with current clinical inhibitors may be beneficial.
8. Paradoxical pathway activation (allosteric priming) is a critical adverse event observed with most RAF inhibitors in the presence of RAS. Its effect on downstream signalling is currently ameliorated with the combined use of MEK inhibitors.
9. Several structurally diverse, next-generation RAF inhibitors are under preclinical or clinical development and may be effective in BRAF-mutant tumours that are resistant to current clinical RAF inhibitors.

要点翻译：

1. 癌蛋白BRAF常因肿瘤中的遗传改变而被激活，进而促进RAF–MEK–ERK信号通路的失调。使用抑制剂靶向BRAF已成为大量癌症患者群体经验证的治疗策略。
2. 单独使用RAF抑制剂或联合MEK抑制剂，在携带BRAF-V600突变激活的黑色素瘤患者中引发了显著疗效并延长了生存期。然而，其疗效受限于耐药性的产生，通常通过促进RAF–ERK信号在药物存在下重新激活的机制。
3. 在非黑色素瘤的BRAF-V600肿瘤中，或携带BRAF-V600以外BRAF改变的肿瘤中，现有临床RAF抑制剂显示出有限疗效。
4. RAF抑制剂具有独特的生化特性，这些特性决定了其宽治疗窗口、靶点毒性及主要耐药机制。
5. RAF二聚化是当前临床RAF抑制剂维莫非尼和达拉非尼产生内在及获得性耐药的常见机制，这些抑制剂将RAF激酶的αC螺旋稳定在OUT位置。此类化合物能有效抑制单体突变BRAF，但无法抑制二聚化RAF。
6. 从结构上看，RAF二聚化导致的抑制剂耐药源于变构抑制效应：当RAF二聚体中一个原体与抑制剂结合后，会阻碍抑制剂与第二个原体的结合。
7. 新一代RAF抑制剂能将RAF激酶的αC螺旋稳定在活性（IN）位置，从而同时抑制RAF单体和二聚体，但预计会因抑制正常细胞中的野生型BRAF而导致治疗窗口变窄。因此，与现有临床抑制剂的联合疗法可能更具优势。
8. 矛盾性通路激活（变构启动）是多数RAF抑制剂在RAS存在时出现的关键不良事件。目前通过联合使用MEK抑制剂可缓解其对下游信号的影响。
9. 多种结构各异的新一代RAF抑制剂正处于临床前或临床开发阶段，可能对现有临床RAF抑制剂耐药的BRAF突变肿瘤有效。

英文摘要：

The discovery that a subset of human tumours is dependent on mutationally deregulated BRAF kinase intensified the development of RAF inhibitors to be used as potential therapeutics. The US Food and Drug Administration (FDA)-approved second-generation RAF inhibitors vemurafenib and dabrafenib have elicited remarkable responses and improved survival of patients with BRAF-V600E/K melanoma, but their effectiveness is limited by resistance. Beyond melanoma, current clinical RAF inhibitors show modest efficacy when used for colorectal and thyroid BRAF-V600E tumours or for tumours harbouring BRAF alterations other than the V600 mutation. Accumulated experimental and clinical evidence indicates that the complex biochemical mechanisms of RAF kinase signalling account both for the effectiveness of RAF inhibitors and for the various mechanisms of tumour resistance to them. Recently, a number of next-generation RAF inhibitors, with diverse structural and biochemical properties, have entered preclinical and clinical development. In this Review, we discuss the current understanding of RAF kinase regulation, mechanisms of inhibitor action and related clinical resistance to these drugs. The recent elucidation of critical structural and biochemical aspects of RAF inhibitor action, combined with the availability of a number of structurally diverse RAF inhibitors currently in preclinical and clinical development, will enable the design of more effective RAF inhibitors and RAF-inhibitor-based therapeutic strategies, tailored to different clinical contexts.

摘要翻译： 

发现一部分人类肿瘤依赖于突变失调的BRAF激酶，加速了RAF抑制剂作为潜在治疗药物的开发。美国食品药品监督管理局（FDA）批准的第二代RAF抑制剂维莫非尼（vemurafenib）和达拉非尼（dabrafenib）在治疗BRAF-V600E/K突变型黑色素瘤患者中取得了显著疗效并延长了生存期，但其疗效受到耐药性的限制。除黑色素瘤外，当前临床使用的RAF抑制剂在治疗结直肠癌和甲状腺BRAF-V600E肿瘤，或携带非V600突变的BRAF变异肿瘤时，疗效较为有限。越来越多的实验和临床证据表明，RAF激酶信号通路的复杂生化机制既决定了RAF抑制剂的有效性，也导致了肿瘤对其产生多种耐药机制。近年来，多种具有不同结构和生化特性的新一代RAF抑制剂已进入临床前和临床开发阶段。在本综述中，我们讨论了当前对RAF激酶调控、抑制剂作用机制及相关临床耐药性的理解。近期对RAF抑制剂作用的关键结构和生化机制的阐明，结合多种结构多样的RAF抑制剂在临床前和临床阶段的可用性，将有助于设计更有效的RAF抑制剂及基于RAF抑制剂的治疗策略，以适应不同的临床情境。

原文链接：

New perspectives for targeting RAF kinase in human cancer