{Reference Type}: Journal Article
{Title}: SULT1A1-dependent sulfonation of alkylators is a lineage-dependent vulnerability of liver cancers.
{Author}: Shi L;Shen W;Davis MI;Kong K;Vu P;Saha SK;Adil R;Kreuzer J;Egan R;Lee TD;Greninger P;Shrimp JH;Zhao W;Wei TY;Zhou M;Eccleston J;Sussman J;Manocha U;Weerasekara V;Kondo H;Vijay V;Wu MJ;Kearney SE;Ho J;McClanaghan J;Murchie E;Crowther GS;Patnaik S;Boxer MB;Shen M;Ting DT;Kim WY;Stanger BZ;Deshpande V;Ferrone CR;Benes CH;Haas W;Hall MD;Bardeesy N;
{Journal}: Nat Cancer
{Volume}: 4
{Issue}: 3
{Year}: 03 2023
{Factor}: 23.177
{DOI}: 10.1038/s43018-023-00523-0
{Abstract}: Adult liver malignancies, including intrahepatic cholangiocarcinoma and hepatocellular carcinoma, are the second leading cause of cancer-related deaths worldwide. Most individuals are treated with either combination chemotherapy or immunotherapy, respectively, without specific biomarkers for 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 liver cancer types. We demonstrate that selectivity is determined by expression of the liver-resident cytosolic sulfotransferase enzyme SULT1A1, which sulfonates YC-1. Sulfonation stimulates covalent binding of YC-1 to lysine residues in protein targets, enriching for RNA-binding factors. Computational analysis defined 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 preclinical development of these agents and point to the broader potential of exploiting SULT1A1 activity for selective targeting strategies.