Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina.
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina.
Am J Pathol. 2019 Oct;189(10):1898-1912. doi: 10.1016/j.ajpath.2019.06.008. Epub 2019 Jul 25.
It is well established that the epidermal growth factor (EGF) receptor, receptor tyrosine-protein kinase erbB-2 (ERBB2)/human EGF receptor 2 (HER2), and, to a lesser extent, ERBB4/HER4, promote the pathogenesis of many types of human cancers. In contrast, the role that ERBB3/HER3, the fourth member of the ERBB family of receptor tyrosine kinases, plays in these diseases is poorly understood and, until recently, underappreciated. In large part, this was because early structural and functional studies suggested that ERBB3 had little, if any, intrinsic tyrosine kinase activity and, thus, was unlikely to be an important therapeutic target. Since then, however, numerous publications have demonstrated an important role for ERBB3 in carcinogenesis, metastasis, and acquired drug resistance. Furthermore, somatic ERBB3 mutations are frequently encountered in many types of human cancers. Dysregulation of ERBB3 trafficking as well as cooperation with other receptor tyrosine kinases further enhance ERBB3's role in tumorigenesis and drug resistance. As a result of these advances in our understanding of the structure and biochemistry of ERBB3, and a growing focus on the development of precision and combinatorial therapeutic regimens, ERBB3 is increasingly considered to be an important therapeutic target in human cancers. In this review, we discuss the unique structural and functional features of ERBB3 and how this information is being used to develop effective new therapeutic agents that target ERBB3 in human cancers.
已证实表皮生长因子（EGF）受体、受体酪氨酸蛋白激酶 erbB-2（ERBB2）/人表皮生长因子受体 2（HER2），以及在较小程度上 ERBB4/HER4，促进了多种类型人类癌症的发病机制。相比之下，受体酪氨酸激酶家族的第四个成员 ERBB3/HER3 在这些疾病中的作用尚未被充分理解，直到最近才被重视。在很大程度上，这是因为早期的结构和功能研究表明 ERBB3 几乎没有内在的酪氨酸激酶活性，如果有的话，因此不太可能成为一个重要的治疗靶点。然而，此后，大量出版物已经证明了 ERBB3 在致癌作用、转移和获得性耐药中的重要作用。此外，体细胞 ERBB3 突变在许多类型的人类癌症中经常发生。ERBB3 转运的失调以及与其他受体酪氨酸激酶的合作进一步增强了 ERBB3 在肿瘤发生和耐药中的作用。由于我们对 ERBB3 的结构和生物化学的理解取得了这些进展，并且越来越关注开发精确和组合治疗方案，因此 ERBB3 被认为是人类癌症中一个重要的治疗靶点。在这篇综述中，我们讨论了 ERBB3 的独特结构和功能特征，以及如何利用这些信息开发针对人类癌症中 ERBB3 的有效新治疗药物。
