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GNE-493 suppresses gastric cancer development by targeting NAT10-mediated ac4C modification of HK2

Tengkai Wang1, Junling Zhen2, Qingao Wei2

  • 1The First Clinical College of Shandong University, No. 44 Wenhua West Road, Jinan, Shandong, 250012, China; Department of Gastroenterology, Qilu Hospital of Shandong University, No. 107 Wenhua West Road, Jinan, Shandong, 250012, China.

Cellular Signalling
|February 22, 2026
PubMed

Insights

A new drug, GNE-493, targets N-acetyltransferase 10 (NAT10) to inhibit gastric cancer growth by blocking glucose metabolism. This approach shows promise against chemoresistant tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Gastric cancer is a leading cause of digestive system malignancy.
  • Chemoresistance complicates gastric cancer treatment, necessitating novel therapeutic strategies.
  • Targeting tumor cell metabolic reprogramming, including aerobic glycolysis, is a promising approach.

Purpose of the Study:

  • To identify novel therapeutic agents targeting gastric cancer metabolism.
  • To investigate the mechanism of action of identified compounds.
  • To evaluate the efficacy of compounds in chemoresistant gastric cancer models.

Main Methods:

  • Drug screening to identify gastric cancer proliferation suppressors.
  • Assessing the impact of GNE-493 on glucose uptake and lactate production.
  • Investigating the direct binding of GNE-493 to NAT10.
  • Analyzing the effect of GNE-493 on N4-acetylcytidine (ac4C) modification of hexokinase 2 (HK2) transcripts.
  • Evaluating GNE-493 efficacy in cisplatin-resistant gastric cancer cell lines.

Main Results:

  • GNE-493, a PI3K inhibitor, potently suppressed gastric cancer cell proliferation.
  • GNE-493 inhibited aerobic glycolysis by reducing glucose uptake and lactate production.
  • GNE-493 directly binds to NAT10, decreasing ac4C modification of HK2.
  • Impaired HK2 stability and translation led to reduced glycolytic flux.
  • GNE-493 showed significant efficacy against cisplatin-resistant gastric cancer cells.

Conclusions:

  • GNE-493 targets the epitranscriptomic regulation of metabolic reprogramming in gastric cancer.
  • Inhibition of NAT10-mediated HK2 acetylation by GNE-493 restrains tumor progression.
  • GNE-493 demonstrates potential to overcome chemoresistance in gastric cancer.
  • This strategy offers a novel therapeutic avenue for gastric cancer patients with high glucose metabolism.
Keywords:
ChemoresistanceGNE-493Gastric cancerGlycolysisac4C acetylation

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