SULT1A1-dependent sulfonation of alkylators is a lineage-dependent vulnerability of liver cancers

Area of Science:

• Oncology
• Biochemistry
• Drug Discovery

Background:

• Adult liver malignancies, including intrahepatic cholangiocarcinoma and hepatocellular carcinoma, are a major global health concern, ranking as the second leading cause of cancer-related deaths.
• Current treatments often lack specific biomarkers for patient selection, leading to suboptimal therapeutic outcomes.

Purpose of the Study:

• To identify novel small molecules with selective activity against liver cancer cell lines.
• To elucidate the mechanism of action and identify biomarkers for selective drug targeting in liver malignancies.

Main Methods:

• High-throughput screening of small molecules against liver cancer cell lines.
• Proteomic analysis to identify drug targets and mechanisms of action.
• In vitro resistance models to assess drug efficacy and selectivity.
• Computational analysis to identify structurally related compounds.

Main Results:

• The small molecule YC-1 demonstrated selective activity against a subset of intrahepatic cholangiocarcinoma and hepatocellular carcinoma cell lines.
• Selectivity was attributed to the expression of the cytosolic sulfotransferase enzyme SULT1A1, which sulfonates YC-1, enhancing its protein binding.
• YC-1 targets primarily RNA-binding factors, and related SULT1A1-activated molecules were identified with distinct target profiles.

Conclusions:

• YC-1 represents a promising lead compound for the development of targeted therapies for liver cancer.
• SULT1A1 expression serves as a predictive biomarker for YC-1 activity.
• Exploiting SULT1A1 activity offers a novel strategy for selective targeting of liver malignancies, with potential for a new class of small molecules.