Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center and the Herbert Irving Comprehensive Cancer Center, New York, NY, USA.
Am J Clin Dermatol. 2019 Jun;20(3):315-323. doi: 10.1007/s40257-018-0414-1.
Metastatic melanoma is a heterogenous disease that has served as a model for the development of both targeted therapy and immunotherapy. KIT-mutated melanoma represents a rare subset, most commonly arising from acral, mucosal, and chronically sun-damaged skin. Additionally, KIT alterations are enriched in the triple wild-type subtype of cutaneous melanoma. Activating alterations of KIT-a transmembrane receptor tyrosine kinase important for cell development, growth, and differentiation-have been shown to be critical to oncogenesis across many tumor subtypes. Following the successes of BRAF-targeted therapy in melanoma and KIT-targeted therapy in gastrointestinal stromal tumors, small-molecule tyrosine kinase inhibitors targeting KIT have been examined in KIT-mutated melanoma. KIT inhibitors that have been investigated in relevant clinical trials in advanced melanoma include imatinib, sunitinib, dasatinib, and nilotinib. In these studies, selected patients with KIT-mutated melanoma were shown to be responsive to therapy with KIT inhibition, especially patients with L576P and K642E mutations. This has led to the incorporation of KIT-targeted therapy in the National Comprehensive Cancer Network guidelines for systemic therapy for metastatic or unresectable melanoma. Current research and development efforts include novel KIT-targeted therapies and testing KIT inhibitors in combination with immunotherapy.
转移性黑色素瘤是一种异质性疾病，它为靶向治疗和免疫治疗的发展提供了模型。KIT 突变型黑色素瘤代表了一个罕见的亚型，最常见于肢端、黏膜和慢性日光损伤的皮肤。此外，KIT 改变在皮肤黑色素瘤的三野生型亚型中富集。KIT-一种对细胞发育、生长和分化至关重要的跨膜受体酪氨酸激酶-的激活改变已被证明对许多肿瘤亚型的癌变至关重要。继 BRAF 靶向治疗在黑色素瘤和 KIT 靶向治疗在胃肠道间质瘤中的成功之后，针对 KIT 的小分子酪氨酸激酶抑制剂已在 KIT 突变型黑色素瘤中进行了研究。在晚期黑色素瘤的相关临床试验中研究的 KIT 抑制剂包括伊马替尼、舒尼替尼、达沙替尼和尼洛替尼。在这些研究中，显示 KIT 突变型黑色素瘤的某些患者对 KIT 抑制治疗有反应，尤其是具有 L576P 和 K642E 突变的患者。这导致 KIT 靶向治疗被纳入国家综合癌症网络转移性或不可切除黑色素瘤系统治疗指南。目前的研究和开发工作包括新型 KIT 靶向疗法和测试 KIT 抑制剂与免疫疗法联合使用。
