Smalley Keiran S M, Sondak Vernon K, Weber Jeffrey S
The Comprehensive Melanoma Research Center and the Department of Cutaneous Oncology, The Moffitt Cancer Center, Tampa, FL, USA.
Histol Histopathol. 2009 May;24(5):643-50. doi: 10.14670/HH-24.643.
As we enter the era of targeted therapy for melanoma, attempts are being made to sub-group tumors on the basis of their driving oncogenic mutations, with the hope of developing truly personalized therapeutic regimens. c-KIT is a receptor tyrosine kinase whose aberrant activation is implicated in the progression of gastrointestinal stromal tumors and some acute myeloid leukemias. The role of c-KIT signaling in melanoma has been controversial; although c-KIT activity is critical to melanocyte development, its expression tends to be lost in most melanomas. Some reports have even shown that the re-expression of c-KIT induces apoptosis in melanoma cell lines. The recent publication of work showing the presence of activating c-KIT mutations in acral and mucosal melanomas, as well as melanomas arising on skin with chronic sun damage, has renewed interest in c-KIT signaling in melanoma. Recent work from our own laboratory has further identified melanomas with constitutive c-KIT signaling activity resulting from c-KIT receptor overexpression. Although the initial clinical trials of the c-KIT inhibitor imatinib mesylate in melanoma were negative, some dramatic responses have been seen in patients with very high c-KIT expression and/or documented activating mutations, fostering the belief that focused studies in patients selected on the basis of c-KIT mutational status will yield more encouraging results. The current review discusses the role of c-KIT signaling in melanoma progression and how this new information can be applied to the targeted therapy of melanoma.
随着我们进入黑色素瘤靶向治疗时代，人们正尝试根据驱动致癌突变对肿瘤进行亚组分类，以期开发出真正个性化的治疗方案。c-KIT是一种受体酪氨酸激酶，其异常激活与胃肠道间质瘤和一些急性髓系白血病的进展有关。c-KIT信号在黑色素瘤中的作用一直存在争议；尽管c-KIT活性对黑素细胞发育至关重要，但其表达在大多数黑色素瘤中往往会丧失。一些报告甚至表明，c-KIT的重新表达会诱导黑色素瘤细胞系凋亡。最近发表的研究表明，在肢端和黏膜黑色素瘤以及慢性阳光损伤皮肤产生的黑色素瘤中存在激活的c-KIT突变，这重新引发了人们对黑色素瘤中c-KIT信号的兴趣。我们自己实验室最近的研究进一步确定了因c-KIT受体过表达而具有组成性c-KIT信号活性的黑色素瘤。尽管甲磺酸伊马替尼在黑色素瘤中的初步临床试验结果为阴性，但在c-KIT表达非常高和/或有记录的激活突变的患者中观察到了一些显著反应，这使人们相信，对根据c-KIT突变状态选择的患者进行重点研究将产生更令人鼓舞的结果。本综述讨论了c-KIT信号在黑色素瘤进展中的作用以及如何将这些新信息应用于黑色素瘤的靶向治疗。
