Kalinsky Kevin, Haluska Frank G
Tufts-New England Medical Center, Cancer Center & the Division of Hematology/Oncology, Boston, MA 02111, USA.
Expert Rev Anticancer Ther. 2007 May;7(5):715-24. doi: 10.1586/14737140.7.5.715.
Metastatic melanoma continues to be a difficult disease to treat. Recent efforts have focused on developing novel, target-directed therapeutic agents. In this review, we discuss the RAS-RAF-MAP kinase and the RAS-PI3K-AKT pathway in detail, as up to 80% of cutaneous melanomas exhibit a BRAF mutation. The preclinical and clinical data regarding BRAF inhibition is reviewed. Other potential targets in these pathways are also discussed. Preclinical data have recently emerged, suggesting that the following subsets of patients have a lower frequency of BRAF mutations: acral, mucosal and cutaneous melanomas with chronic sun-induced damage. These lesions have a higher frequency of KIT mutations. However, cutaneous melanomas without chronic sun damage have a higher frequency of BRAF mutations and are not noted to have KIT mutations. It is possible that the appropriate subset of patients may respond differently to available targeted therapies and clinical trials are in development to assess the utility of KIT inhibition in these patients.
转移性黑色素瘤仍然是一种难以治疗的疾病。最近的努力集中在开发新型的、靶向治疗药物。在本综述中，我们详细讨论了RAS-RAF-MAP激酶和RAS-PI3K-AKT通路，因为高达80%的皮肤黑色素瘤存在BRAF突变。我们回顾了关于BRAF抑制的临床前和临床数据。还讨论了这些通路中的其他潜在靶点。最近出现的临床前数据表明，以下患者亚组的BRAF突变频率较低：肢端、黏膜和有慢性阳光损伤的皮肤黑色素瘤。这些病变的KIT突变频率较高。然而，没有慢性阳光损伤的皮肤黑色素瘤BRAF突变频率较高，且未发现有KIT突变。合适的患者亚组可能对现有的靶向治疗有不同反应，目前正在开展临床试验以评估KIT抑制对这些患者的效用。
