Combination of EphA2- and Wee1-Targeted Therapies in Endometrial Cancer.

Autor: Dasari SK; Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.; National Institute of Animal Biotechnology, Hyderabad 500029, India., Joseph R; Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Umamaheswaran S; Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.; UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Mangala LS; Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Bayraktar E; Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Rodriguez-Aguayo C; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Wu Y; Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Nguyen N; High-Throughput Research and Screening Center, Center for Translational Cancer Research, Texas A&M Health Science Center, Institute of Biosciences and Technology, Houston, TX 77030, USA., Powell RT; High-Throughput Research and Screening Center, Center for Translational Cancer Research, Texas A&M Health Science Center, Institute of Biosciences and Technology, Houston, TX 77030, USA., Sobieski M; High-Throughput Research and Screening Center, Center for Translational Cancer Research, Texas A&M Health Science Center, Institute of Biosciences and Technology, Houston, TX 77030, USA., Liu Y; Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Chowdhury MA; Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Amero P; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Stephan C; High-Throughput Research and Screening Center, Center for Translational Cancer Research, Texas A&M Health Science Center, Institute of Biosciences and Technology, Houston, TX 77030, USA., Lopez-Berestein G; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Westin SN; Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Sood AK; Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2023 Feb 15; Vol. 24 (4). Date of Electronic Publication: 2023 Feb 15.
DOI: 10.3390/ijms24043915
Abstrakt: 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.
Databáze: MEDLINE
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