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

Author:

Dasari Santosh K.12,Joseph Robiya1,Umamaheswaran Sujanitha13,Mangala Lingegowda S.1,Bayraktar Emine1,Rodriguez-Aguayo Cristian4ORCID,Wu Yutuan1,Nguyen Nghi5,Powell Reid T.5,Sobieski Mary5,Liu Yuan1,Chowdhury Mamur A.1,Amero Paola4ORCID,Stephan Clifford5ORCID,Lopez-Berestein Gabriel4,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. National Institute of Animal Biotechnology, Hyderabad 500029, India

3. UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

4. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

5. 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

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.

Funder

NIH

American Cancer Society Research Professor Award

Frank McGraw Memorial Chair in Cancer Research

Dunwoody Fund

Gordon Fund

NIH-NCI

CPRIT-funded Combinatorial Drug Discovery Program

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

Reference20 articles.

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3. EphA2 overexpression correlates with poor prognosis in esophageal squamous cell carcinoma;Miyazaki;Int. J. Cancer,2003

4. Protein B61 as a new growth factor: Expression of B61 and up-regulation of its receptor epithelial cell kinase during melanoma progression;Easty;Cancer Res.,1995

5. Predictive value of the EphA2 receptor tyrosine kinase in lung cancer recurrence and survival;Kinch;Clin. Cancer Res.,2003

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