Faculty, Staff and Student Publications
Publication Date
2-15-2023
Journal
International Journal of Molecular Sciences
Abstract
EphA2 tyrosine kinase is upregulated in many cancers and correlated with poor survival of patients, including those with endometrial cancer. EphA2-targeted drugs have shown modest clinical benefit. To improve the therapeutic response to such drugs, we performed a high-throughput chemical screen to discover novel synergistic partners for EphA2-targeted therapeutics. Our screen identified the Wee1 kinase inhibitor, MK1775, as a synergistic partner to EphA2, and this finding was confirmed using both in vitro and in vivo experiments. We hypothesized that Wee1 inhibition would sensitize cells to EphA2-targeted therapy. Combination treatment decreased cell viability, induced apoptosis, and reduced clonogenic potential in endometrial cancer cell lines. In vivo Hec1A and Ishikawa-Luc orthotopic mouse models of endometrial cancer showed greater anti-tumor responses to combination treatment than to either monotherapy. RNASeq analysis highlighted reduced cell proliferation and defective DNA damage response pathways as potential mediators of the combination's effects. In conclusion, our preclinical findings indicate that Wee1 inhibition can enhance the response to EphA2-targeted therapeutics in endometrial cancer; this strategy thus warrants further development.
Keywords
Animals, Female, Humans, Mice, Antineoplastic Agents, Apoptosis, Cell Cycle Proteins, Cell Line, Tumor, Cell Proliferation, Endometrial Neoplasms, Protein Kinase Inhibitors, Protein-Tyrosine Kinases, Receptor, EphA2, Molecular Targeted Therapy, endometrial cancer, EphA2, Wee1
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Medical Sciences Commons, Obstetrics and Gynecology Commons, Oncology Commons, Women's Health Commons
Comments
Supplementary Materials
Data Availability Statement
PMID: 36835335