Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.
Curr Opin Oncol. 2010 May;22(3):178-83. doi: 10.1097/cco.0b013e32833888ee.
The identification of mutations in signal transduction pathways that are central in melanoma pathophysiology has provided new therapeutic targets for drug development. The purpose of this review is to define those oncogenes for which there are preclinical data supporting clinical trials and to summarize results from clinical investigations.
CKIT mutations were first reported in 2005 but are present in only a small subpopulation of melanoma patients. The validation of inhibitors developed in gastrointestinal stromal tumors has taken several years, but recent evidence suggests that responses can be seen in CKIT mutant melanoma. First reported in 2002, BRAF is mutated in 50% of all melanomas and subsets of other cancers. The melanoma field is leading the clinical trials evaluating the value of targeting BRAF and MEK in BRAF mutant tumors. Results from the first clinical trial with a potent and selective BRAF inhibitor clearly show the therapeutic promise of this approach.
Larger clinical trials are needed to fully define the efficacy of BRAF and CKIT-directed therapy in melanoma, but early results suggest that this strategy will transform treatment options. Additional potential targets have been identified, and clinical trials evaluating novel drugs against them are underway.
目的综述： 黑色素瘤病理生理学中的信号转导通路的突变的鉴定为药物开发提供了新的治疗靶点。本文的目的是确定那些具有支持临床试验的临床前数据的致癌基因，并总结临床研究的结果。
最新发现： 2005 年首次报道了 CKIT 突变，但仅存在于一小部分黑色素瘤患者中。在胃肠道间质瘤中开发的抑制剂的验证需要几年的时间，但最近的证据表明，在 CKIT 突变的黑色素瘤中可以看到反应。BRAF 于 2002 年首次报道，在所有黑色素瘤和其他癌症的亚组中均发生突变。黑色素瘤领域正在引领评估针对 BRAF 突变肿瘤的 BRAF 和 MEK 靶向治疗价值的临床试验。首个具有强大和选择性 BRAF 抑制剂的临床试验结果清楚地显示了这种方法的治疗潜力。
总结： 需要更大的临床试验来充分确定 BRAF 和 CKIT 靶向治疗在黑色素瘤中的疗效，但早期结果表明，这种策略将改变治疗选择。已经确定了其他潜在的靶点，正在进行针对它们的新型药物的临床试验。
