Homolog of epidermal growth factor receptor 2 (HER2/ErbB2) is overexpressed in cancers of the breast, colon, and lung, and is associated with poorer patient prognosis with ~20% of breast cancers. HER2 is principally activated by heterodimerization with other members of the epidermal growth factor receptor (EGFR/ErbB) family. Tumors that also express another member of this receptor family, homolog of epidermal growth factor receptor 3 (HER3/ErbB3), can escape HER2-targeted treatment, and heterodimerization of HER2 with HER3 is particularly mitogenic. The long-term goal of this project is to gain an improved understanding of the nature of HER2-containing heterodimers and why these heterodimers are so closely linked to a variety of cancers.
The first aim of this project is to determine the structure of the extracellular domains of HER2-containing heterodimers. Heterodimers of the extracellular domains of HER2 and other members of this family, with a focus on heterodimers containing HER3, will be driven and stabilized by antibody fusion proteins.
The second aim of this project is to characterize the activation of nearly full-length HER2 in the context of HER2/HER3 heterodimers in vitro. I expect that these structural and biochemical studies will reveal unique aspects of the heterodimerization and activation of these receptors. As HER2 is a target of many successful cancer treatments, an improved understanding of this receptor may inform and direct current treatment strategies.
Overexpression of homolog of epidermal growth factor receptor 2 (HER2/ErbB2) is associated with poorer patient prognosis in ~20% of breast cancers and is also implicated in cancers of the colon and lung. HER2 is the target of many successful cancer treatments, but tumors that also express another member of this receptor family, homolog of epidermal growth factor receptor 3 (HER3/ErbB3), can escape HER2-targeted treatment. The goal of this project is to gain an improved understanding of how these receptors interact which may then direct and improve current treatment modalities.
