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Dissertation
Improving the use of AURKA and WEE1 inhibitors in head and neck squamous cell carcinoma
Doctor of Philosophy (Ph.D.), Drexel University
Nov 2025
DOI:
https://doi.org/10.17918/00011263
Abstract
Head and Neck Squamous Cell Carcinoma (HNSCC) is a deadly form of cancer. AURKA and WEE1 inhibitors have long attracted attention for the treatment of HNSCC. AURKA and WEE1 are regulators of the cell cycle. The use of either AURKA inhibitors or WEE1 inhibitors in clinical trials for HNSCC is limited by toxicity and more research is necessary to improve their use. First, we show the activity of NN-01-195, a novel chimeric inhibitor that combines an AURKA inhibitor with an HSP90 inhibitor. This chimeric inhibitor utilizes the HSP90-binding moiety to increase retention in cancer cells, which highly express HSP90. The linked AURKA inhibitor is used as a cytotoxic payload. We show that NN-01-195 can bind and inhibit both AURKA and HSP90. NN-01-195 is also well tolerated in mice, is retained in xenograft tissue, and is highly effective at controlling tumor volume. We propose the use of NN-01-195 for the treatment of HNSCC. Next, we show the impact of WEE1 inhibition on HNSCC. WEE1 inhibition increases the expression of replication stress-associated proteins. Because replication stress can be associated with metabolic reprogramming, we next tested if WEE1 inhibition could influence glucose metabolism. Using Seahorse glycolytic stress assays and mass spectrometry-based assays, we found that WEE1 inhibition depresses glycolysis, elevates the quantity of glycolytic intermediates, and elevates the flux of glycolytic intermediates into alternative metabolic pathways that assist in resolving replication stress. In total, this work improves our understanding of both AURKA and WEE1 inhibitors for their use in treating HNSCC.
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Details
- Title
- Improving the use of AURKA and WEE1 inhibitors in head and neck squamous cell carcinoma
- Creators
- Theodore T. Nguyen
- Contributors
- Erica Golemis (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University
- Number of pages
- 118 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991022154573404721