My research is focused on the mechanism and implications of glycosylation in HER2+ breast cancer. HER2+ breast cancer is caused by the overexpression of the HER2 protein, leading to upregulation of cell proliferation. Approximately 20% of patients are diagnosed with HER2+ breast cancer, and around 20-50% of patients become resistant to treatment. Common treatments of HER2+ breast cancer include small molecule inhibitors, antibody treatments such as Trastuzumab, and antibody-drug conjugates (ADCs) such as Trastuzumab-Deruxtecan (T-Dxd). A common small molecule inhibitor used during treatment is Neratinib, a tyrosine kinase inhibitor that blocks signaling from the HER2 protein. There are many hypotheses as to why this resistance occurs, one being glycosylation. Glycosylation is the addition of sugar molecules, or glycans, to the cell surface. The addition of sugar molecules to the cell surface form a glycocalyx, which aids in regulating key physiopathological processes throughout the body. It is hypothesized that in cancer cells, there are defects in glycosylation, leading to a thicker, dysregulated glycocalyx. Because of this thick glycocalyx, typical treatments such as Trastuzumab, a large antibody, cannot interact with the HER2 protein that rests of the cell surface, meaning tumor proliferation continues. However, this idea cannot be applied to small molecule inhibitors such as Neratinib, which are still able to move throughout the glycocalyx. My project will focus on understanding what are the impacts of inhibiting glycosylation on neratinib response and epidermal growth factor (EGF) signaling in HER2+ breast cancer cells.
Northeastern University
