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Theranostics 2021; 11(14):6873-6890. doi:10.7150/thno.49235 This issue Cite

Research Paper

Pharmacological inhibition of noncanonical EED-EZH2 signaling overcomes chemoresistance in prostate cancer

Xin Li^1,2, Lajos Gera³, Shumin Zhang⁴, Yanhua Chen^2,5, Lei Lou⁶, Lauren Marie Wilson⁶, Zhong-Ru Xie⁶, Giuseppe Sautto⁷, Degang Liu⁸, Alira Danaher¹, Kenza Mamouni², Yang Yang^2,9, Yuhong Du¹⁰, Haian Fu^10,11, Omer Kucuk^4,11, Adeboye O. Osunkoya^4,12, Jia Zhou¹³, Daqing Wu^1,2,4,14✉

1. Center for Cancer Research and Therapeutic Development and Department of Biological Sciences, Clark Atlanta University, Atlanta, GA, USA.
2. Molecular Oncology and Biomarkers Program, Georgia Cancer Center; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
3. Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Anschutz Medical Campus, School of Medicine, Aurora, CO, USA.
4. Department of Urology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.
5. Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
6. School of Electrical and Computer Engineering, College of Engineering, University of Georgia, Athens, GA, USA.
7. Center for Vaccines and Immunology, University of Georgia, Athens, GA, USA.
8. Sartorius Corporation, Bohemia, NY, USA.
9. Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
10. Department of Pharmacology and Chemical Biology, and Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA, USA.
11. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.
12. Departments of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
13. Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
14. MetCure Therapeutics LLC, Atlanta, GA, USA.

✉ Corresponding author: Dr. Daqing Wu, Center for Cancer Research and Therapeutic Development and Department of Biological Sciences, Clark Atlanta University, Atlanta, GA, USA. Email: dwuedu; Phone: (404)880-6337; Fax: (404)880-6756.

Abstract

Rationale: Chemoresistance is a major obstacle in prostate cancer (PCa) treatment. We sought to understand the underlying mechanism of PCa chemoresistance and discover new treatments to overcome docetaxel resistance.

Methods: We developed a novel phenotypic screening platform for the discovery of specific inhibitors of chemoresistant PCa cells. The mechanism of action of the lead compound was investigated using computational, molecular and cellular approaches. The in vivo toxicity and efficacy of the lead compound were evaluated in clinically-relevant animal models.

Results: We identified LG1980 as a lead compound that demonstrates high selectivity and potency against chemoresistant PCa cells. Mechanistically, LG1980 binds embryonic ectoderm development (EED), disrupts the interaction between EED and enhancer of zeste homolog 2 (EZH2), thereby inducing the protein degradation of EZH2 and inhibiting the phosphorylation and activity of EZH2. Consequently, LG1980 targets a survival signaling cascade consisting of signal transducer and activator of transcription 3 (Stat3), S-phase kinase-associated protein 2 (SKP2), ATP binding cassette B 1 (ABCB1) and survivin. As a lead compound, LG1980 is well tolerated in mice and effectively suppresses the in vivo growth of chemoresistant PCa and synergistically enhances the efficacy of docetaxel in xenograft models.

Conclusions: These results indicate that pharmacological inhibition of EED-EZH2 interaction is a novel strategy for the treatment of chemoresistant PCa. LG1980 and its analogues have the potential to be integrated into standard of care to improve clinical outcomes in PCa patients.

Keywords: prostate cancer, chemoresistance, EED inhibitor, EZH2 signaling, drug discovery

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