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Article

EphA2- and HDAC-Targeted Combination Therapy in Endometrial Cancer

by
Robiya Joseph
1,†,
Santosh K. Dasari
1,†,‡,
Sujanitha Umamaheswaran
1,2,
Lingegowda S. Mangala
1,
Emine Bayraktar
1,
Cristian Rodriguez-Aguayo
3,
Yutuan Wu
1,
Nghi Nguyen
4,
Reid T. Powell
4,
Mary Sobieski
4,
Yuan Liu
1,
Mark Seungwook Kim
1,
Sara Corvigno
1,
Katherine Foster
1,
Pahul Hanjra
1,2,
Thanh Chung Vu
1,
Mamur A. Chowdhury
1,
Paola Amero
3,
Clifford Stephan
4,
Gabriel Lopez-Berestein
3,
Shannon N. Westin
1 and
Anil K. Sood
1,*add Show full author list remove Hide full author list
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
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
‡
Current address: National Institute of Animal Biotechnology, Hyderabad 500029, India.
Int. J. Mol. Sci. 2024, 25(2), 1278; https://doi.org/10.3390/ijms25021278
Submission received: 2 December 2023 / Revised: 5 January 2024 / Accepted: 14 January 2024 / Published: 20 January 2024
(This article belongs to the Special Issue New Insights into Endometrial Cancer 2023)
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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.
Keywords: endometrial cancer; EphA2; histone deacetylase endometrial cancer; EphA2; histone deacetylase

Share and Cite

MDPI and ACS Style

Joseph, R.; Dasari, S.K.; Umamaheswaran, S.; Mangala, L.S.; Bayraktar, E.; Rodriguez-Aguayo, C.; Wu, Y.; Nguyen, N.; Powell, R.T.; Sobieski, M.; et al. EphA2- and HDAC-Targeted Combination Therapy in Endometrial Cancer. Int. J. Mol. Sci. 2024, 25, 1278. https://doi.org/10.3390/ijms25021278

AMA Style

Joseph R, Dasari SK, Umamaheswaran S, Mangala LS, Bayraktar E, Rodriguez-Aguayo C, Wu Y, Nguyen N, Powell RT, Sobieski M, et al. EphA2- and HDAC-Targeted Combination Therapy in Endometrial Cancer. International Journal of Molecular Sciences. 2024; 25(2):1278. https://doi.org/10.3390/ijms25021278

Chicago/Turabian Style

Joseph, Robiya, Santosh K. Dasari, Sujanitha Umamaheswaran, Lingegowda S. Mangala, Emine Bayraktar, Cristian Rodriguez-Aguayo, Yutuan Wu, Nghi Nguyen, Reid T. Powell, Mary Sobieski, and et al. 2024. "EphA2- and HDAC-Targeted Combination Therapy in Endometrial Cancer" International Journal of Molecular Sciences 25, no. 2: 1278. https://doi.org/10.3390/ijms25021278

APA Style

Joseph, R., Dasari, S. K., Umamaheswaran, S., Mangala, L. S., Bayraktar, E., Rodriguez-Aguayo, C., Wu, Y., Nguyen, N., Powell, R. T., Sobieski, M., Liu, Y., Kim, M. S., Corvigno, S., Foster, K., Hanjra, P., Vu, T. C., Chowdhury, M. A., Amero, P., Stephan, C., ... Sood, A. K. (2024). EphA2- and HDAC-Targeted Combination Therapy in Endometrial Cancer. International Journal of Molecular Sciences, 25(2), 1278. https://doi.org/10.3390/ijms25021278

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