Liver lineage confers sensitivity of cancer cells to sulfonation-dependent alkylators

Adult liver malignancies, including intrahepatic cholangiocarcinoma and hepatocellular carcinoma, are the 2nd leading cause of cancer related death worldwide. The majority of patients are currently treated with either combination chemotherapy or immunotherapy, respectively, without specific biomarkers for patient selection. Here, using high-throughput screens, proteomics, and in vitro resistance models, we identify the small molecule, YC-1, as selectively active against a defined subset of cell lines derived from both major liver cancer types. We demonstrate that selectivity in vitro and in vivo is determined by expression of a human cytosolic sulfotransferase – the liver resident enzyme SULT1A1, which sulfonates YC-1. Sulfonation stimulates covalent binding of YC-1 to lysine residues in protein targets, enriching for RNA binding factors. Using computational analysis as well as structural modeling, we also define a wider group of structurally related SULT1A1-activated small molecules with distinct target profiles, which together constitute an untapped small molecule class. These studies provide a foundation for pre-clinical development of these agents and point to the broader potential of exploiting the liver lineage enzyme SULT1A1 for selective targeting strategies. Overall design: Two SULT1A1 expressing, IDH1 mutant human cholangiocarcinoma cell lines RBE and SNU1079 were used to study YC-1 induced transcriptomic alterations. Specific experimental design includes YC-1 and DMSO vehicle treated conditions at early (6 hour) and late (16 hour) time points, with three biological replicates for each condition. In total, 24 samples were collected for RNA extraction and subsequently RNA sequencing.