The heavily glycosylated mucin proteins are ubiquitously expressed at epithelial and endothelial cell surfaces, but can become dysregulated in disease. MUC1 is frequently dysregulated in carcinomas, and its creative cancer-promoting abilities make it a uniquely challenging therapeutic target. A relatively new strategy called targeted protein degradation, using endogenous or exogenous protein degradation machinery, shows promise for eliminating “undruggable” proteins like MUC1.
What are Mucins?
If you’re thinking that “mucin” sounds a lot like “mucus,” you’re on the right track. Mucins are highly glycosylated proteins expressed at epithelial and endothelial surfaces to protect against physical damage and pathogens. These proteins are the key component of mucus, the viscous fluid that lines mucosal surfaces to help provide these protective functions.
What you may not know is that mucins have also been implicated in cancer, specifically in carcinomas. One member of the mucin family, MUC1, is dysregulated in over half of carcinomas diagnosed each year in the United States. Efforts to target MUC1 using antibodies, CAR-T cells, or small molecule drugs are in development, but face a number of challenges thanks to MUC1’s redundant tumor-progressive abilities.
Designing Targeted Protein Degradation
An exciting avenue for challenging targets like MUC1 is targeted protein degradation (TPD). TPD typically involves bispecific molecules that are able to direct unwanted proteins to the cell’s endogenous protein degradation machinery. However, for this approach to work, target proteins must be expressed in the cytosol. MUC1 is primarily secreted or associated with the cell membrane, rather than being expressed in the cytosol.
In a recent Nature Biotechnology paper from Nobel laureate Carolyn Bertozzi’s research group, Pedram et. al. describe engineering a bacterial protease that can achieve TPD of cancer cell-associated mucins without having to recruit endogenous degradation machinery. By fusing this protease containing glycan- and peptide-based selectivity for mucins with a nanobody, the authors were able to successfully target cancer cells.
Strategies for “Undruggable” Cancer Mutations
The targeted proteases reduced cancer cell growth both in vitro and in mouse models of primary and metastatic breast cancer. This is an exciting validation of TPD for targeting extracellular proteins, as nearly all extracellular proteins are glycosylated (including MUC1). Glycosylation is frequently altered in disease states, opening up opportunities to engineer degradation strategies specific to certain diseased cell types or glycosylation patterns.
TPD as a general strategy is particularly exciting in the space of classically “undruggable” protein targets because it completely eliminates the protein and thus eliminates all of its associated downstream effects. While elimination is not a suitable strategy for all disease-associated proteins, with enough target specificity, it can be an excellent therapeutic strategy for continued development.
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Jane Cook, Biochemist & Content Writer, Bridge Informatics
Jane Cook, the leading Content Writer for Bridge Informatics, has written over 100 articles on the latest topics and trends for the bioinformatics community. Jane’s broad and deep interdisciplinary molecular biology experience spans developing biochemistry assays to genomics. Prior to joining Bridge, Jane held research assistant roles in biochemistry research labs across a variety of therapeutic areas. While obtaining her B.A. in Biochemistry from Trinity College in Dublin, Ireland, Jane also studied journalism at New York University’s Arthur L. Carter Journalism Institute. As a native Texan, she embraces any challenge that comes her way. Jane hails from Dallas but returns to Ireland any and every chance she gets. If you’re interested in reaching out, please email [email protected] or [email protected].