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.

中文翻译：

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针对人类癌症中RAF激酶的新观点

人类肿瘤的一个子集依赖于突变失调的BRAF激酶的发现加剧了RAF抑制剂被用作潜在治疗剂的发展。美国食品药品监督管理局（FDA）批准的第二代RAF抑制剂vemurafenib和dabrafenib已引起BRAF-V600E / K黑色素瘤患者显着反应并改善了其生存率，但其有效性受到耐药性的限制。除黑色素瘤外，当前的临床RAF抑制剂在用于大肠癌和甲状腺BRAF-V600E肿瘤或具有除V600突变以外的BRAF改变的肿瘤时，显示适度的疗效。积累的实验和临床证据表明，RAF激酶信号传导的复杂生化机制既可以解释RAF抑制剂的有效性，也可以解释肿瘤对其的多种耐药机制。最近，许多具有不同结构和生化特性的下一代RAF抑制剂已进入临床前和临床开发。在这篇综述中，我们讨论了目前对RAF激酶调节，抑制剂作用机制以及对这些药物的相关临床耐药性的了解。最近阐明了RAF抑制剂作用的关键结构和生化方面，以及目前在临床前和临床开发中可获得的多种结构多样的RAF抑制剂，