WNTinib is a multi-kinase inhibitor with specificity against β-catenin mutant hepatocellular carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Hepatocellular carcinoma (HCC) is a major global cause of cancer mortality.
• A significant subset of HCC cases (30%) harbor CTNNB1 mutations, lacking specific targeted therapies.
• Existing treatments for HCC often have limited efficacy and broad side effect profiles.

Purpose of the Study:

• To identify a novel, selective therapeutic agent for CTNNB1-mutated HCC.
• To elucidate the mechanism of action for a newly identified kinase inhibitor, WNTinib.
• To evaluate the efficacy and therapeutic index of WNTinib in preclinical models of HCC.

Main Methods:

• Screening of HCC organoids using chemical libraries derived from clinical multi-kinase inhibitor scaffolds.
• Multiomic analyses, target engagement studies, and rescue experiments.
• In vitro and in vivo efficacy studies in human and murine models of CTNNB1-mutated HCC.

Main Results:

• Identification of WNTinib, a highly selective kinase inhibitor for CTNNB1-mutated HCC.
• WNTinib demonstrates superior efficacy compared to existing clinical kinase inhibitors.
• The drug inhibits KIT/mitogen-activated protein kinase (MAPK) signaling and leverages EZH2 for durable transcriptional repression, avoiding compensatory feedback loops.

Conclusions:

• WNTinib represents a potent and selective therapeutic strategy for CTNNB1-mutated HCC.
• The drug's mechanism involves precise targeting of the KIT/MAPK/EZH2 pathway.
• WNTinib offers a promising new treatment with a wide therapeutic index for a challenging subset of liver cancer.