New perspectives for targeting RAF kinase in human cancer.
New perspectives for targeting RAF kinase in human cancer.
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DOI：
10.1038/nrc.2017.79
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发表时间：
2017-11
期刊：
影响因子：
--
通讯作者：
Poulikakos PI
中科院分区：
文献类型：
--
作者：
Karoulia Z;Gavathiotis E;Poulikakos PI
人类肿瘤的一个子集依赖于突变失调的BRAF激酶的发现加强了RAF抑制剂作为潜在治疗剂的开发。美国食品和药物管理局（FDA）批准的第二代RAF抑制剂vemurafenib和dabrafenib已经引起了显着的反应，并改善了BRAF-V600 E/K黑色素瘤患者的生存率，但其有效性受到耐药性的限制。除了黑色素瘤，目前的临床RAF抑制剂在用于结直肠和甲状腺BRAF-V600 E肿瘤或具有BRAF改变而不是V600突变的肿瘤时显示出适度的疗效。累积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解释了RAF抑制剂的有效性，也解释了肿瘤对它们的各种耐药性机制。近年来，许多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。在这篇综述中，我们讨论了目前对RAF激酶调节的理解，抑制剂作用的机制和对这些药物的相关临床耐药性。RAF抑制剂作用的关键结构和生物化学方面的最近阐明，结合目前在临床前和临床开发中的许多结构多样的RAF抑制剂的可用性，将使得能够设计更有效的RAF抑制剂和基于RAF抑制剂的治疗策略，针对不同的临床背景。
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.
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影响因子：
4.3
作者：
Basile KJ;Le K;Hartsough EJ;Aplin AE
通讯作者：
Aplin AE
影响因子：
4.2
作者：
Baines AT;Xu D;Der CJ
通讯作者：
Der CJ
影响因子：
20.3
作者：
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通讯作者：
Rollins, Barrett J.
DOI：
10.1073/pnas.95.16.9214
发表时间：
1998-08-04
影响因子：
11.1
作者：
Cutler, RE;Stephens, RM;Morrison, DK
通讯作者：
Morrison, DK
影响因子：
28.2
作者：
Chen, Shih-Hsun;Zhang, Youyan;Peng, Sheng-Bin
通讯作者：
Peng, Sheng-Bin