Nuclear Localization of Receptor Tyrosine Kinases in Cancers

Receptor tyrosine kinases (RTKs) are a major type of cell surface receptors that modulate crucial intracellular signal transduction via extracellular ligand binding. To date, human RTKs consist of 20 subfamilies in which most of them have been considered as therapeutic targets in cancers [1]. For instance, among the ErbB family RTKs, over-expression and/or constitutive activation of EGF receptor (EGFR)/ErbB1, ErbB2, and ErbB3 are frequently observed in many tumors of epithelial origin. All of the ErbB family members, except ErbB4 with an unclear oncogenic role, are well-recognized oncoproteins involved in aggressive cancer behaviors, such as cancer initiation, tumor growth, metastasis, chemotherapeutic resistance, and poor patient survival. Accordingly, two major types of anti-cancer therapy targeting EGFR and ErbB2, ectodomain-binding antibodies (e.g., cetuximab, trastuzumab, ado-trastuzumab emtansine, and pertuzumab) and small-molecule tyrosine kinase inhibitors (TKIs; e.g., erlotinib, gefitinib, and lapatinib), have been developed with promising clinical outcomes, and many of them have been approved by the US Food and Drug Administration