Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
Oncogene. 2013 May 9;32(19):2373-9. doi: 10.1038/onc.2012.345. Epub 2012 Sep 3.
The mitogen-activated protein kinase (MAPK) pathway is critical to oncogenic signaling in the majority of patients with malignant melanoma. Driver mutations in both NRAS and BRAF have important implications for prognosis and treatment. The development of inhibitors to mediators of the MAPK pathway, including those to CRAF, BRAF, and MEK, has led to major advances in the treatment of patients with melanoma. In particular, the selective BRAF inhibitor vemurafenib has been shown to improve overall survival in patients with tumors harboring BRAF mutations. However, the duration of benefit is limited in many patients and highlights the need for understanding the limitations of therapy in order to devise more effective strategies. MEK inhibitors have proven to particularly active in BRAF mutant melanomas also. Emerging knowledge about mechanisms of resistance as well as a more complete understanding of the biology of MAPK pathway signaling provides insight into rational combination regimens and sequences of molecularly targeted therapies.
丝裂原活化蛋白激酶（MAPK）通路对大多数恶性黑色素瘤患者的致癌信号转导至关重要。NRAS 和 BRAF 中的驱动突变对预后和治疗具有重要意义。MAPK 通路介质的抑制剂的开发，包括 CRAF、BRAF 和 MEK 的抑制剂，已经使黑色素瘤患者的治疗取得了重大进展。特别是，选择性 BRAF 抑制剂 vemurafenib 已被证明可改善携带 BRAF 突变的肿瘤患者的总生存期。然而，许多患者的受益持续时间有限，这凸显了需要了解治疗的局限性，以便制定更有效的策略。MEK 抑制剂也已被证明在 BRAF 突变黑色素瘤中特别有效。关于耐药机制的新知识以及对 MAPK 通路信号转导生物学的更全面理解，为合理的联合治疗方案和分子靶向治疗的顺序提供了思路。
