Structural basis for EGFR transmembrane signaling and its implications in therapeutic development

Epidermal growth factor receptor (EGFR) and its homologs (HER2, HER3, and HER4) belong to receptor tyrosine kinase (RTK) superfamily. They regulate important cellular functions, including cell growth, differentiation, and proliferation. Dysregulation of these receptor transmembrane signaling, either by mutation or by overexpression, leads to oncogenesis. Therefore, they are validated therapeutic targets in the treatment of various cancers, such as lung and breast cancers. Although significant progress has been achieved in understanding the basis for oncogenesis associated with EGFR kinase mutation, less is known about how the transmembrane signaling is dysregulated by EGFR or HER2 overexpression, and how EGFR or HER2 overexpression contributes to oncogenesis and drug resistance. Herein, we review the progress in the structural studies of these receptors’ transmembrane signaling and the development of their targeted therapeutics.