Department of Oncology, St James's Hospital, Dublin, Ireland Division of Biomedical Sciences, St George's, University of London, London, UK.
Pigment Cell Melanoma Res. 2011 Jun;24(3):446-61. doi: 10.1111/j.1755-148X.2011.00836.x. Epub 2011 Mar 3.
Receptor tyrosine kinases (RTKs) and their downstream signalling pathways have long been hypothesized to play key roles in melanoma development. A decade ago, evidence was derived largely from animal models, RTK expression studies and detection of activated RAS isoforms in a small fraction of melanomas. Predictions that overexpression of specific RTKs implied increased kinase activity and that some RTKs would show activating mutations in melanoma were largely untested. However, technological advances including rapid gene sequencing, siRNA methods and phospho-RTK arrays now give a more complete picture. Mutated forms of RTK genes including KIT, ERBB4, the EPH and FGFR families and others are known in melanoma. Additional over- or underexpressed RTKs and also protein tyrosine phosphatases (PTPs) have been reported, and activities measured. Complex interactions between RTKs and PTPs are implicated in the abnormal signalling driving aberrant growth and survival in malignant melanocytes, and indeed in normal melanocytic signalling including the response to ultraviolet radiation. Kinases are considered druggable targets, so characterization of global RTK activity in melanoma should assist the rational development of tyrosine kinase inhibitors for clinical use.
受体酪氨酸激酶（RTKs）及其下游信号通路长期以来一直被认为在黑色素瘤的发展中起着关键作用。十年前，这些证据主要来自于动物模型、RTK 表达研究以及在一小部分黑色素瘤中检测到激活的 RAS 同工型。人们预测，特定 RTKs 的过度表达意味着激酶活性增加，并且一些 RTKs 会在黑色素瘤中出现激活突变，但这些预测在很大程度上未经证实。然而，包括快速基因测序、siRNA 方法和磷酸化 RTK 阵列在内的技术进步现在提供了更完整的图景。在黑色素瘤中已知存在 RTK 基因的突变形式，包括 KIT、ERBB4、EPH 和 FGFR 家族等。此外，还报告了其他过度表达或低表达的 RTKs 和蛋白酪氨酸磷酸酶（PTPs），并测量了它们的活性。RTKs 和 PTPs 之间的复杂相互作用参与了驱动恶性黑色素瘤中异常生长和存活的异常信号传导，事实上也参与了包括对紫外线辐射反应在内的正常黑色素细胞信号传导。激酶被认为是可成药的靶点，因此对黑色素瘤中全局 RTK 活性的特征分析应该有助于合理开发用于临床的酪氨酸激酶抑制剂。
