文章：

靶向RAF激酶用于癌症治疗：BRAF突变黑色素瘤及其他

Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond

原文发布日期：2014-06-24

DOI: 10.1038/nrc3760

类型: Review Article

开放获取: 否

要点：

1. Mutationally activated BRAF is expressed in melanoma, glioblastoma, thyroid, lung and colon cancers and in a subset of haematological malignancies.
2. The most common BRAF mutation leads to the substitution of a glutamic acid for valine at amino acid 600 (V600E) in the kinase domain of the protein. This substitution mimics phosphorylation of the activation loop, thereby inducing constitutive BRAF protein kinase activity.
3. Point mutations in the related ARAF and CRAF protein kinases, although very rare, have been reported as oncogenic drivers in some human cancers. In addition to point mutation, gene fusion events are reported to activate BRAF and CRAF.
4. Numerous non-V600E alterations in BRAF have been reported in cancer and in a rare developmental disorder. Many of these promote kinase activity by relieving autoinhibitory mechanisms or promote activation of other RAF isoforms in a RAS-dependent manner.
5. ATP-competitive BRAF kinase inhibitors are currently under investigation for the treatment of BRAF-mutated cancers. However, to date, efficacy is limited to a subset of melanomas owing to primary or adaptive resistance mechanisms in colorectal and thyroid cancers that reactivate signalling downstream of receptor tyrosine kinases.
6. In clinical trials of BRAF-mutated melanoma, BRAF inhibitors tend to induce high rates of response that show transient durability due to the onset of drug-resistant disease.
7. Acquired resistance to BRAF-V600E inhibitors is strikingly complex but frequently involves reactivation of MEK–ERK MAP kinase signalling. Drug resistance due to overexpression of oncogenic BRAF-V600E leads to 'oncogene overdose' following cessation of drug administration — a phenomenon that could be clinically exploitable to forestall the onset of drug resistance.
8. The efficacy of RAF inhibitors in tumours with other RAF mutations is mostly unknown, although preclinical studies indicate varied responses that are inhibitor-specific and depend on the biochemical mechanism of oncogene activation.

要点翻译：

1. 突变激活的BRAF在黑色素瘤、胶质母细胞瘤、甲状腺癌、肺癌和结肠癌以及部分血液恶性肿瘤中表达。
2. 最常见的BRAF突变导致该蛋白激酶结构域第600位氨基酸的缬氨酸被谷氨酸替代（V600E）。这种替代模拟了激活环的磷酸化，从而诱导BRAF蛋白激酶组成性激活。
3. 尽管非常罕见，但相关ARAF和CRAF蛋白激酶的点突变已被报道为某些人类癌症的致癌驱动因素。除点突变外，基因融合事件也被报道可激活BRAF和CRAF。
4. 在癌症和一种罕见发育障碍中，已报道大量非V600E的BRAF变异。其中许多通过解除自身抑制机制促进激酶活性，或以RAS依赖性方式促进其他RAF亚型的激活。
5. 目前正在研究ATP竞争性BRAF激酶抑制剂用于治疗BRAF突变癌症。但迄今为止，由于结直肠癌和甲状腺癌中存在原发性或适应性耐药机制导致受体酪氨酸激酶下游信号重新激活，该疗法仅对部分黑色素瘤有效。
6. 在BRAF突变黑色素瘤的临床试验中，BRAF抑制剂往往能诱导高缓解率，但由于耐药性疾病的发生，这种缓解持续时间短暂。
7. 对BRAF-V600E抑制剂获得性耐药机制极为复杂，但通常涉及MEK-ERK MAP激酶信号通路的重新激活。致癌性BRAF-V600E过表达导致的耐药性会在停药后引发"癌基因过量"现象——这一现象或可被临床利用以延缓耐药发生。
8. RAF抑制剂对其他RAF突变肿瘤的疗效大多未知，尽管临床前研究表明其反应存在差异，这种差异具有抑制剂特异性并取决于癌基因激活的生化机制。

英文摘要：

The identification of mutationally activated BRAF in many cancers altered our conception of the part played by the RAF family of protein kinases in oncogenesis. In this Review, we describe the development of BRAF inhibitors and the results that have emerged from their analysis in both the laboratory and the clinic. We discuss the spectrum of RAF mutations in human cancer and the complex interplay between the tissue of origin and the response to RAF inhibition. Finally, we enumerate mechanisms of resistance to BRAF inhibition that have been characterized and postulate how strategies of RAF pathway inhibition may be extended in scope to benefit not only the thousands of patients who are diagnosed annually with BRAF-mutated metastatic melanoma but also the larger patient population with malignancies harbouring mutationally activated RAF genes that are ineffectively treated with the current generation of BRAF kinase inhibitors.

摘要翻译： 

在许多癌症中发现BRAF突变激活，改变了我们对RAF蛋白激酶家族在肿瘤发生中作用的认识。在本综述中，我们描述了BRAF抑制剂的研发过程，并总结了实验室与临床研究中获得的成果。我们讨论了人类癌症中RAF突变的谱系，以及组织起源与RAF抑制反应之间的复杂相互作用。最后，我们列举了已阐明的BRAF抑制剂耐药机制，并推测如何通过拓展RAF通路抑制策略，不仅使每年新诊断的数千例BRAF突变转移性黑色素瘤患者受益，也让更多携带突变激活RAF基因、却对现有BRAF激酶抑制剂治疗无效的恶性肿瘤患者获益。

原文链接：

Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond