2. Academic Validation
  3. Identification of a Novel Substrate for eEF2K and the AURKA-SOX8 as the Related Pathway in TNBC

Identification of a Novel Substrate for eEF2K and the AURKA-SOX8 as the Related Pathway in TNBC

  • Adv Sci (Weinh). 2025 Feb 14:e2412985. doi: 10.1002/advs.202412985.
Xiaoya Wan 1 2,  Rong Gong 1 2,  Xiaobao Zhao 3,  Yizhi Li 1 2,  Tianjiao Shan 1 2,  Changxin Zhong 1 2,  Rongfeng Zhu 3,  Zonglin Chen 4,  Shilong Jiang 5,  Linhao He 1 2,  Shijun Cao 1 2,  Sheng Tian 3,  Jinming Yang 6,  Na Ye 3 7,  Wenjun Yi 4 8,  Yan Cheng 1 2 9 10 11
Affiliations

Affiliations

  • 1 Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
  • 2 Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, 410011, China.
  • 3 Department of Medicinal Chemistry, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
  • 4 Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
  • 5 Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, 410028, China.
  • 6 Department of Cancer Biology and Toxicology, Department of Pharmacology, College of Medicine and Markey Cancer Center, University of Kentucky, Lexington, KY, 40536, USA.
  • 7 Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Soochow University, Suzhou, 215123, China.
  • 8 Clinical Research Center For Breast Disease In Hunan Province, Changsha, 410011, China.
  • 9 FuRong Laboratory, Changsha, Hunan, 410078, China.
  • 10 Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, Changsha, 410011, China.
  • 11 NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, 410008, China.
PMID: 39950798 DOI: 10.1002/advs.202412985
Abstract

Eukaryotic elongation factor 2 kinase (eEF2K) has been considered as a putative target for Cancer therapy; however, the underlying mechanisms of eEF2K in triple-negative breast Cancer (TNBC) progression remain to be fully elucidated. In this study, it is shown that eEF2K is highly expressed in TNBC and is associated with poor prognosis. In vitro, in vivo, and patient-derived Organoid experiments demonstrate that knockdown of eEF2K significantly impedes progression of TNBC. Proteomic analysis and confirmation experiments reveal that eEF2K positively regulates the mRNA and protein expressions of sex-determining region Y-box 8 (SOX8). Mechanistically, eEF2K binds to and phosphorylates Aurora Kinase A (AURKA) at S391, a newly identified phosphorylation site critical for maintaining AURKA protein stability and kinase activity. Moreover, the compound C1, a molecular glue to degrade eEF2K, is optimized by designing and synthesizing its derivatives using reasonable structure-based optimization approach. The new compound C4 shows better ability to degrade eEF2K and stronger anti-cancer activity than C1. These findings not only uncover the pivotal role of the eEF2K/AURKA/SOX8 axis in TNBC progression, but also provide a promising lead compound for developing novel drug for treatment of TNBC.

Keywords

AURKA; SOX8; eEF2K; eEF2K degrader; triple‐negative breast cancer.

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