Lo Roger S, Shi Hubing
Department of Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Methods Mol Biol. 2014;1102:163-74. doi: 10.1007/978-1-62703-727-3_10.
(V600)BRAF mutation was identified as an ideal target for clinical therapy due to its indispensable roles in supporting melanoma initiation and progression. Despite the fact that BRAF inhibitors (BRAFi) can elicit anti-tumor responses in the majority of treated patients and confer overall survival benefits, acquired drug resistance is a formidable obstacle to long-term management of the disease. Several aberrant events including RTK upregulation, NRAS mutation, mutant BRAF amplification or alternative splicing, and MEK mutation have been reported as acquired BRAFi resistance mechanisms. Clinially, detection of these resistance mechanisms help understand drug response patterns and help guide combinatorial therapeutic strategies. Therefore, quick and accurate diagnosis of the resistant mechanisms in tumor biopsies has become an important starting point for personalized therapy. In this chapter, we review the major acquired BRAFi resistance mechanisms, highlight their therapeutic implications, and provide the diagnostic methods from clinical samples.
（V600）BRAF突变因其在支持黑色素瘤起始和进展中不可或缺的作用而被确定为临床治疗的理想靶点。尽管BRAF抑制剂（BRAFi）可在大多数接受治疗的患者中引发抗肿瘤反应并带来总生存获益，但获得性耐药是该疾病长期管理的一个巨大障碍。包括RTK上调、NRAS突变、突变型BRAF扩增或可变剪接以及MEK突变在内的几种异常事件已被报道为获得性BRAFi耐药机制。临床上，检测这些耐药机制有助于了解药物反应模式并指导联合治疗策略。因此，快速准确地诊断肿瘤活检中的耐药机制已成为个性化治疗的重要起点。在本章中，我们回顾了主要的获得性BRAFi耐药机制，强调其治疗意义，并提供临床样本的诊断方法。
