Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
Harvard Medical School, Boston, MA, USA.
Yonsei Med J. 2020 Jul;61(7):562-571. doi: 10.3349/ymj.2020.61.7.562.
Melanoma, originating from epidermal melanocytes, is a heterogeneous disease that has the highest mortality rate among all types of skin cancers. Numerous studies have revealed the cause of this cancer as related to various somatic driver mutations, including alterations in -a proto-oncogene encoding for a transmembrane receptor tyrosine kinase. Although accounting for only 3% of all melanomas, mutations in c-KIT are mostly derived from acral, mucosal, and chronically sun-damaged melanomas. As an important factor for cell differentiation, proliferation, and survival, inhibition of c-KIT has been exploited for clinical trials in advanced melanoma. Here, apart from the molecular background of c-KIT and its cellular functions, we will review the wide distribution of alterations in with a catalogue of more than 40 mutations reported in various articles and case studies. Additionally, we will summarize the association of mutations with clinicopathologic features (age, sex, melanoma subtypes, anatomic location, etc.), and the differences of mutation rate among subgroups. Finally, several therapeutic trials of c-KIT inhibitors, including imatinib, dasatinib, nilotinib, and sunitinib, will be analyzed for their success rates and limitations in advanced melanoma treatment. These not only emphasize c-KIT as an attractive target for personalized melanoma therapy but also propose the requirement for additional investigational studies to develop novel therapeutic trials co-targeting c-KIT and other cytokines such as members of signaling pathways and immune systems.
黑色素瘤起源于表皮黑素细胞，是一种异质性疾病，其死亡率在所有皮肤癌中最高。大量研究表明，这种癌症的病因与各种体细胞驱动突变有关，包括编码跨膜受体酪氨酸激酶的原癌基因的改变。虽然在所有黑色素瘤中只占 3%，但 c-KIT 的突变主要来源于肢端、黏膜和慢性日光损伤的黑色素瘤。作为细胞分化、增殖和存活的重要因素，抑制 c-KIT 已被用于晚期黑色素瘤的临床试验。在这里，除了 c-KIT 的分子背景及其细胞功能外，我们将回顾 的广泛改变，其中包括在各种文章和病例研究中报道的超过 40 种突变。此外，我们将总结 突变与临床病理特征（年龄、性别、黑色素瘤亚型、解剖部位等）的关系，以及亚组间突变率的差异。最后，我们将分析几种 c-KIT 抑制剂的治疗试验，包括伊马替尼、达沙替尼、尼洛替尼和舒尼替尼，分析它们在晚期黑色素瘤治疗中的成功率和局限性。这些不仅强调了 c-KIT 作为个性化黑色素瘤治疗的有吸引力的靶点，还提出了需要进行额外的研究性研究，以开发针对 c-KIT 和其他细胞因子（如信号通路和免疫系统成员）的新的联合治疗试验。
