1] Department of Medicine, Georgetown University School of Medicine, Washington, DC, USA [2] Hematology and Oncology, MedStar Washington Hospital Center, Washington, DC, USA.
1] Division of Hematology and Oncology, Georgetown University School of Medicine, Washington, DC, USA [2] Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC, USA.
Clin Pharmacol Ther. 2014 Jan;95(1):24-31. doi: 10.1038/clpt.2013.197. Epub 2013 Sep 30.
The discovery of activating BRAF mutations in melanomas has led to the investigation of small molecular inhibitors targeting BRAF mutation and MEK, a downstream protein within the mitogen-activated protein kinase (MAPK) pathway. This article reviews the role of mutant BRAF in melanoma and summarizes the results of clinical trials evaluating inhibitors of BRAF and MEK in BRAF-mutant melanoma. We further describe recent findings on the mechanisms of resistance to BRAF inhibitors and discuss ongoing efforts to combine BRAF inhibitors with other targeted agents. Finally, we review the results of immunotherapy in BRAF-mutant melanoma and address the current status of efforts to either combine or determine the optimal sequence of these two distinct treatment approaches. Although the recent advances in melanoma therapy have been dramatic, greater understanding of melanoma biology coupled with the successful development of several new treatments and combination regimens will further improve patient outcomes in the future.
BRAF 突变在黑色素瘤中的发现促使人们研究针对 BRAF 突变和丝裂原活化蛋白激酶（MAPK）通路下游蛋白 MEK 的小分子抑制剂。本文综述了突变型 BRAF 在黑色素瘤中的作用，并总结了评估 BRAF 和 MEK 抑制剂在 BRAF 突变型黑色素瘤中的临床试验结果。我们进一步描述了 BRAF 抑制剂耐药的机制，并讨论了目前将 BRAF 抑制剂与其他靶向药物联合应用的努力。最后，我们回顾了 BRAF 突变黑色素瘤免疫治疗的结果，并探讨了联合应用或确定这两种不同治疗方法的最佳顺序的现状。尽管黑色素瘤治疗的最新进展令人瞩目，但对黑色素瘤生物学的更深入了解以及几种新的治疗方法和联合方案的成功开发，将在未来进一步改善患者的预后。
