EphA2- and HDAC-Targeted Combination Therapy in Endometrial Cancer
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Published:2024-01-20
Issue:2
Volume:25
Page:1278
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Joseph Robiya1, Dasari Santosh K.1, Umamaheswaran Sujanitha12, Mangala Lingegowda S.1, Bayraktar Emine1, Rodriguez-Aguayo Cristian3ORCID, Wu Yutuan1, Nguyen Nghi4, Powell Reid T.4, Sobieski Mary4, Liu Yuan1, Kim Mark Seungwook1, Corvigno Sara1, Foster Katherine1, Hanjra Pahul12, Vu Thanh Chung1, Chowdhury Mamur A.1, Amero Paola3ORCID, Stephan Clifford4, Lopez-Berestein Gabriel3, Westin Shannon N.1ORCID, Sood Anil K.1
Affiliation:
1. Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 2. UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 3. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 4. 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
Abstract
Endometrial cancer is the most frequent malignant tumor of the female reproductive tract but lacks effective therapy. EphA2, a receptor tyrosine kinase, is overexpressed by various cancers including endometrial cancer and is associated with poor clinical outcomes. In preclinical models, EphA2-targeted drugs had modest efficacy. To discover potential synergistic partners for EphA2-targeted drugs, we performed a high-throughput drug screen and identified panobinostat, a histone deacetylase inhibitor, as a candidate. We hypothesized that combination therapy with an EphA2 inhibitor and panobinostat leads to synergistic cell death. Indeed, we found that the combination enhanced DNA damage, increased apoptosis, and decreased clonogenic survival in Ishikawa and Hec1A endometrial cancer cells and significantly reduced tumor burden in mouse models of endometrial carcinoma. Upon RNA sequencing, the combination was associated with downregulation of cell survival pathways, including senescence, cyclins, and cell cycle regulators. The Axl-PI3K-Akt-mTOR pathway was also decreased by combination therapy. Together, our results highlight EphA2 and histone deacetylase as promising therapeutic targets for endometrial cancer.
Funder
National Institutes of Health/National Cancer Institute NIH the American Cancer Society Research Professor Award, the Frank McGraw Memorial Chair in Cancer Research, the Dunwoody Fund, the Gordon Fund, and NIH-NCI FWC Amy Krouse Rosenthal award National Center for Advancing Translational Sciences CPRIT-funded Combinatorial Drug Discovery Program
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
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