Mechanisms of ERBB3 Action in Human Neoplasia

It is well established that the epidermal growth factor receptor, ERBB2/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. Further, 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 enhances 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.