Puzanov Igor, Flaherty Keith T
Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA.
Semin Cutan Med Surg. 2010 Sep;29(3):196-201. doi: 10.1016/j.sder.2010.06.005.
Immunotherapy and chemotherapy benefit few patients with metastatic melanoma, and even fewer experience durable survival benefit. These poor results may come from treating all melanomas as though they are biologically homogeneous. Recently, it has been shown that targeting specific activated tyrosine kinases (oncogenes) can have striking clinical benefits in patients with melanoma. In 2002, a V600E mutation of the BRAF serine/threonine kinase was described as present in more than 50% of all melanomas. The mutation appeared to confer a dependency by the melanoma cancer cell on activated signaling through mitogen-activated protein kinase pathway. The frequency and focality of this mutation (>95% of all BRAF mutations being at V600 position) suggested its importance in melanoma pathophysiology and potential as a target for therapy. The recent results of a phase 1 study with PLX4032/RG7204, a small molecule RAF inhibitor, confirm this hypothesis. Mucosal and acral-lentiginous melanomas, comprising 3% of all melanomas, frequently harbor activating mutations of c-kit and drugs targeting this mutation seem to confer similar benefits for these types of tumors. Here we provide an overview of the targeted therapy development in melanoma with emphasis on BRAF inhibition because of its prevalence and possibility of transforming the care of many melanoma patients.
免疫疗法和化疗对少数转移性黑色素瘤患者有益，而能获得持久生存益处的患者更少。这些不佳结果可能源于将所有黑色素瘤都视为生物学上同质的来进行治疗。最近，研究表明，针对特定激活的酪氨酸激酶（致癌基因）进行治疗，对黑色素瘤患者可能会产生显著的临床益处。2002年，有人描述称，超过50%的黑色素瘤中存在BRAF丝氨酸/苏氨酸激酶的V600E突变。该突变似乎使黑色素瘤癌细胞依赖于通过丝裂原活化蛋白激酶途径的激活信号传导。这种突变的频率和集中性（所有BRAF突变中>95%位于V600位置）表明其在黑色素瘤病理生理学中的重要性以及作为治疗靶点的潜力。一项使用小分子RAF抑制剂PLX4032/RG7204的1期研究的最新结果证实了这一假设。黏膜型和肢端雀斑样痣型黑色素瘤占所有黑色素瘤的3%，经常存在c-kit激活突变，针对该突变的药物似乎对这些类型的肿瘤也有类似益处。在此，我们概述黑色素瘤靶向治疗的发展情况，重点介绍BRAF抑制，因为其普遍性以及有可能改变许多黑色素瘤患者的治疗方式。
