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

Xiaoya Wan1,2, Rong Gong1,2, Xiaobao Zhao3

  • 1Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|February 14, 2025
PubMed

Insights

Eukaryotic elongation factor 2 kinase (eEF2K) drives triple-negative breast cancer (TNBC) by regulating AURKA and SOX8. Targeting eEF2K with new compounds like C4 shows promise for TNBC therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Triple-negative breast cancer (TNBC) remains a therapeutic challenge with poorly understood progression mechanisms.
  • Eukaryotic elongation factor 2 kinase (eEF2K) is a potential cancer target, but its role in TNBC requires further investigation.

Purpose of the Study:

  • To elucidate the role and mechanism of eEF2K in TNBC progression.
  • To identify novel therapeutic strategies targeting eEF2K in TNBC.

Main Methods:

  • Expression analysis of eEF2K in TNBC tissues.
  • In vitro, in vivo, and patient-derived organoid experiments to assess eEF2K function.
  • Proteomic analysis to identify eEF2K-regulated pathways.
  • Biochemical assays to confirm eEF2K-AURKA interaction and phosphorylation.
  • Structure-based drug design and synthesis of eEF2K degraders.

Main Results:

  • eEF2K is highly expressed in TNBC and linked to poor prognosis.
  • eEF2K knockdown significantly inhibits TNBC progression.
  • eEF2K positively regulates SOX8 expression via AURKA phosphorylation at S391, stabilizing AURKA.
  • A novel compound C4 demonstrates enhanced eEF2K degradation and anti-cancer activity compared to C1.

Conclusions:

  • The eEF2K/AURKA/SOX8 axis is crucial for TNBC progression.
  • Targeting eEF2K represents a promising therapeutic avenue for TNBC.
  • Compound C4 is a potential lead for developing new TNBC drugs.
Keywords:
AURKASOX8eEF2KeEF2K degradertriple‐negative breast cancer

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