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  3. AGPAT4 targeted covalent inhibitor potentiates targeted therapy to overcome cancer cell plasticity in hepatocellular carcinoma mouse models

AGPAT4 targeted covalent inhibitor potentiates targeted therapy to overcome cancer cell plasticity in hepatocellular carcinoma mouse models

  • Sci Transl Med. 2025 Jul 30;17(809):eadn9472. doi: 10.1126/scitranslmed.adn9472.
Kai-Yu Ng 1 2,  Tin-Yan Koo 1,  Ianto Bosheng Huang 1 2,  Terence Kin-Wah Lee 3,  Tsz-Lok Fong 1,  Ya Gao 1,  Tin-Lok Wong 1 4,  Yuan Gao 5,  Jing-Ping Yun 6,  Xin-Yuan Guan 4 7 8 9,  Ming Liu 10 11,  Clive Yik-Sham Chung 1 4 12,  Stephanie Ma 1 2 4 7 8 13
Affiliations

Affiliations

  • 1 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
  • 2 Laboratory for Synthetic Chemistry and Chemical Biology, Hong Kong Science and Technology Park, Hong Kong, China.
  • 3 Department of Applied Biology and Chemical Technology, Hong Kong Polytechnic University, Hong Kong, China.
  • 4 State Key Laboratory of Liver Research, University of Hong Kong, Hong Kong, China.
  • 5 State Key Laboratory of Cancer Biology, Biotechnology Centre, School of Pharmacy, Fourth Military Medical University, Xián, China.
  • 6 Department of Pathology, Sun Yat-Sen University Cancer Centre, Guangzhou, China.
  • 7 University of Hong Kong - Shenzhen Hospital, Shenzhen, China.
  • 8 Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen University, Guangzhou, China.
  • 9 Department of Clinical Oncology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
  • 10 Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.
  • 11 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, China.
  • 12 Centre for Oncology and Immunology, Hong Kong Science and Technology Park, Hong Kong, China.
  • 13 Centre for Translational and Stem Cell Biology, Hong Kong Science and Technology Park, Hong Kong, China.
PMID: 40737432 DOI: 10.1126/scitranslmed.adn9472
Abstract

The development of cancerous cells leads to considerable changes in metabolic processes to meet the demands of tumor growth. Tumor lineage plasticity has been identified as a key factor in therapy resistance and tumor recurrence. Herein, we showed one aspect of this plasticity to be abnormal glycerophospholipid metabolism, specifically the presence of a metabolic protein called 1-acylglycerol-3-phosphate o-acyltransferase 4 (AGPAT4). We identified AGPAT4 as an oncofetal protein that is abundant in embryonic stem cells and hepatocellular carcinoma (HCC) tumor cells but is low or absent in most normal tissues. We demonstrated that AGPAT4 is a functional regulator of tumor lineage plasticity, which correlates with enhanced metastasis and resistance to sorafenib. Heightened plasticity was induced as a result of increased AGPAT4-mediated conversion of LPA (lysophosphatidic acid) to phosphatidic acid (PA), which then acts on its downstream mTOR/S6K/S6 signaling pathway. Inhibition of Agpat4 by the AAV8-mediated liver-directed strategy in an immunocompetent HCC mouse model reduced tumorigenicity and stemness and sensitized tumors to sorafenib. Through a chemical biology approach, a cysteine-reacting compound that specifically targets AGPAT4 at the Cys228 residue and therefore hinders its Acyltransferase activity was identified and found to work synergistically with sorafenib in suppressing HCC in tumor xenograft models derived from patients with preclinical HCC and sorafenib-resistant HCC. Toxicological analysis revealed minimal side effects associated with the covalent inhibitor. In conclusion, the plasticity of tumor lineages induced by AGPAT4 represents a potential target for HCC treatment and could expand the effectiveness of sorafenib treatment, offering new possibilities for HCC therapy.

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