Breakthrough in Liver Cancer Treatment: Targeted Therapy Counters Cell Plasticity in Mouse Models

Researchers at The University of Hong Kong’s School of Biomedical Sciences have achieved a significant advancement in liver cancer therapy, specifically for hepatocellular carcinoma (HCC), the most common form of liver cancer known for its resistance to treatment and high recurrence rates. This disease predominantly affects populations in Southeast Asia and China.

The study, published in Science Translational Medicine, uncovered a novel mechanism that enables HCC to grow more aggressively and evade existing therapeutic strategies. Central to this discovery was the identification of a metabolic pathway involving a protein called AGPAT4. This protein, which is highly expressed in both embryonic stem cells and HCC tumor cells but rarely in normal tissues, acts as a switch that increases cancer cell flexibility—known as tumor plasticity—contributing to treatment resistance and tumor recurrence.

Specifically, AGPAT4 facilitates the conversion of lysophosphatidic acid (LPA) into phosphatidic acid (PA), activating signaling pathways like mTOR that promote tumor growth and survival. Blocking AGPAT4 in mouse models slowed tumor progression and made the cancer more responsive to sorafenib, a standard drug for liver cancer.

Building on these insights, the research team developed CL26, a small-molecule inhibitor that specifically targets AGPAT4. When used alongside sorafenib in preclinical models based on patient-derived tumors, CL26 significantly suppressed tumor growth with minimal side effects, indicating its potential safety and effectiveness.

These promising results suggest that targeting AGPAT4 could enhance current treatments for HCC, overcoming tumor plasticity and resistance mechanisms. Future steps include larger preclinical studies to evaluate the safety and efficacy of CL26, with the ultimate goal of advancing to clinical trials. This development represents a hopeful leap forward in personalized therapy for liver cancer patients who currently have limited options.

Source: https://medicalxpress.com/news/2025-08-therapy-cell-plasticity-liver-cancer.html