文章：

MEK1和MEK2抑制剂与癌症治疗：漫长而曲折的道路

MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road

原文发布日期：2015-09-24

DOI: 10.1038/nrc4000

类型: Review Article

开放获取: 否

要点：

1. The RAS-regulated RAF–MEK–ERK signalling pathway transmits signals from growth factor receptors to the nucleus and other organelles to regulate cell proliferation, differentiation, survival and invasion.
2. ERK pathway architecture places MEK1 and MEK2 in a unique position, where they process inputs from multiple upstream activating kinases so that ERK1 and ERK2 may be activated alone (following RAF activation) or together with other kinases such as JNK or p38.
3. The majority of cancers exhibit hyper-activation of the ERK pathway owing to deregulation (mutation, gene fusions, amplification, and so on) of receptor tyrosine kinases, RAS, BRAF, CRAF, MEK1 or MEK2 or owing to the loss of negative pathway regulators, such as dual-specificity phosphatases (DUSPs) and NF1. In many cases, these mutations confer a range of pathway dependencies including classical 'oncogene addiction', providing a rationale for ERK pathway inhibitors as therapeutic agents.
4. Melanomas carrying the mutation encoding BRAF-V600E are almost invariably addicted to BRAF activity, and first-generation BRAF inhibitors (BRAFis) have transformed the treatment of this disease. However, an inability to inhibit signalling by RAF dimers drives acquired resistance, and paradoxical RAF activation in tumours with wild-type BRAF limits the success or wider application of BRAFis.
5. As RAF signalling proceeds via the activation of MEK1 and MEK2, and RAF-addicted tumour cells are also MEK-addicted, MEK1 and MEK2 are also attractive drug targets. Additionally, MEK1 and MEK2 contain a unique hydrophobic pocket adjacent to their ATP-binding site, which allows the binding of potent, non-ATP competitive, allosteric inhibitors. However, MEK1 and MEK2 are rarely mutated in cancer, so MEK inhibitors (MEKis) will not preferentially inhibit MEK1 and MEK2 in tumour cells compared with normal tissue; this may contribute to normal tissue toxicity.
6. The first MEKi to receive US Food and Drug Administration approval, trametinib, is being used to treat BRAF-mutant melanoma in combination with first-generation BRAFis. A range of additional MEKis are in late-stage clinical development and exhibit various modes of action; for example, some MEKis can prevent the phosphorylation of MEK1 and MEK2 by RAF, and others can disrupt RAF–MEK1/MEK2 complexes. The extent to which these properties influence clinical activity is currently unclear.
7. Factors that limit the efficacy of MEKis include loss of feedback inhibition and consequent reactivation of ERK1 and ERK2. Intrinsic resistance can be driven by the activation of parallel pathways, including the PI3K pathway, whereas acquired resistance to MEKis arises through the emergence of mutations in MEK1 or MEK2 or the amplification of BRAF^V600E or mutant RAS.
8. Adaptation and resistance to MEKis can be overcome by combinations with other targeted agents, including intrapathway dual inhibition. Clinical trials assessing MEKis in combination with other targeted agents or conventional chemotherapy are ongoing.

要点翻译：

1. RAS调控的RAF-MEK-ERK信号通路将生长因子受体信号传递至细胞核及其他细胞器，从而调控细胞增殖、分化、存活与侵袭。
2. ERK通路的结构特征使MEK1和MEK2处于独特位置：它们整合来自多个上游激活激酶的输入信号，使得ERK1和ERK2既可被单独激活（继发于RAF激活），也可与JNK或p38等其他激酶共同激活。
3. 大多数癌症因受体酪氨酸激酶、RAS、BRAF、CRAF、MEK1或MEK2的失调（突变、基因融合、扩增等），或负向通路调控因子（如双特异性磷酸酶DUSPs和NF1）缺失而呈现ERK通路过度激活。这些突变常导致一系列通路依赖性，包括典型的“癌基因成瘾”，这为ERK通路抑制剂作为治疗药物提供了理论依据。
4. 携带BRAF-V600E编码突变的黑色素瘤几乎无一例外地依赖于BRAF活性，第一代BRAF抑制剂（BRAFis）已彻底改变该疾病的治疗格局。然而，由于无法抑制RAF二聚体信号传导导致获得性耐药，且在BRAF野生型肿瘤中出现反常的RAF激活，限制了BRAFis的疗效及更广泛应用。
5. 鉴于RAF信号通过激活MEK1和MEK2传递，且RAF依赖性肿瘤细胞同样依赖MEK，MEK1和MEK2也成为有吸引力的药物靶点。此外，MEK1和MEK2的ATP结合位点附近存在独特疏水口袋，可结合强效非ATP竞争性变构抑制剂。但由于MEK1和MEK2在癌症中罕有突变，MEK抑制剂（MEKis）对肿瘤细胞与正常组织中MEK的抑制缺乏选择性，这可能引发正常组织毒性。
6. 首个获美国FDA批准的MEKi曲美替尼，目前与第一代BRAFis联合用于治疗BRAF突变型黑色素瘤。多种其他MEKis已进入临床研发后期，它们作用机制各异：例如部分MEKis能阻止RAF对MEK1和MEK2的磷酸化，另一些则可破坏RAF-MEK1/MEK2复合物。这些特性对临床活性的影响程度目前尚不明确。
7. 限制MEKis疗效的因素包括反馈抑制缺失及随之而来的ERK1和ERK2再激活。内在耐药可由平行通路（如PI3K通路）激活驱动，而获得性耐药则源于MEK1或MEK2突变、BRAFV600E扩增或RAS突变的出现。
8. 通过与其他靶向药物（包括通路内双重抑制）联用，可克服对MEKis的适应性与耐药性。目前正在开展MEKis与其他靶向药物或常规化疗联合治疗的临床试验。

英文摘要：

The role of the ERK signalling pathway in cancer is thought to be most prominent in tumours in which mutations in the receptor tyrosine kinases RAS, BRAF, CRAF, MEK1 or MEK2 drive growth factor-independent ERK1 and ERK2 activation and thence inappropriate cell proliferation and survival. New drugs that inhibit RAF or MEK1 and MEK2 have recently been approved or are currently undergoing late-stage clinical evaluation. In this Review, we consider the ERK pathway, focusing particularly on the role of MEK1 and MEK2, the 'gatekeepers' of ERK1/2 activity. We discuss their validation as drug targets, the merits of targeting MEK1 and MEK2 versus BRAF and the mechanisms of action of different inhibitors of MEK1 and MEK2. We also consider how some of the systems-level properties (intrapathway regulatory loops and wider signalling network connections) of the ERK pathway present a challenge for the success of MEK1 and MEK2 inhibitors, discuss mechanisms of resistance to these inhibitors, and review their clinical progress.

摘要翻译： 

ERK信号通路在癌症中的作用被认为在受体酪氨酸激酶RAS、BRAF、CRAF、MEK1或MEK2发生突变的肿瘤中最为突出，这些突变驱动了不依赖生长因子的ERK1和ERK2激活，进而导致细胞异常增殖与存活。近期，抑制RAF或MEK1/MEK2的新药已获批上市，或正处于后期临床评估阶段。本文综述ERK通路，尤其聚焦于MEK1和MEK2——ERK1/2活性的‘守门人’。我们讨论其作为药物靶点的验证、相较于BRAF靶向MEK1/2的优势，以及不同MEK1/2抑制剂的作用机制。同时，我们探讨ERK通路的系统级特性（通路内调控环路及更广泛信号网络连接）对MEK1/2抑制剂疗效构成的挑战，阐述其耐药机制，并回顾其临床进展。

原文链接：

MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road