Holderfield Matthew, Deuker Marian M, McCormick Frank, McMahon Martin
1] Helen Diller Family Comprehensive Cancer Center and Department of Cell and Molecular Pharmacology, University of California, San Francisco, California 94158, USA. [2].
Helen Diller Family Comprehensive Cancer Center and Department of Cell and Molecular Pharmacology, University of California, San Francisco, California 94158, USA.
Nat Rev Cancer. 2014 Jul;14(7):455-67. doi: 10.1038/nrc3760.
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.
在许多癌症中对突变激活的BRAF的鉴定改变了我们对RAF蛋白激酶家族在肿瘤发生中所起作用的认识。在本综述中，我们描述了BRAF抑制剂的研发情况以及在实验室和临床研究中对其分析所得到的结果。我们讨论了人类癌症中RAF突变的范围以及肿瘤起源组织与对RAF抑制反应之间的复杂相互作用。最后，我们列举了已明确的对BRAF抑制的耐药机制，并推测RAF通路抑制策略如何扩大适用范围，从而不仅使每年数千名被诊断为BRAF突变转移性黑色素瘤的患者受益，还能让更多携带突变激活RAF基因且当前一代BRAF激酶抑制剂治疗无效的恶性肿瘤患者受益。
