A Targetable Pathway to Eliminate TRA-1-60+/TRA-1-81+ Chemoresistant Cancer Cells

Abstract

Abstract Chemoresistance is a primary cause of treatment failure in pancreatic cancer. Identifying cell surface markers specifically expressed in chemoresistant cancer cells (CCCs) could facilitate targeted therapies to overcome chemoresistance. We performed an antibody-based screen and found that TRA-1–60 and TRA-1–81, two ‘stemness’ cell surface markers, are highly enriched in CCCs. Furthermore, TRA-1–60+/TRA-1–81+ cells are chemoresistant compared to TRA-1–60–/TRA-1–81– cells. Transcriptome profiling identified UGT1A10, shown to be both necessary and sufficient to maintain TRA-1–60/TRA-1–81 expression and chemoresistance. From a high-content chemical screen, we identified Cymarin, which downregulates UGT1A10, eliminates TRA-1–60/TRA-1–81 expression, and increases chemosensitivity both in vitro and in vivo. Finally, TRA-1–60/TRA-1–81 expression is highly specific in primary cancer tissue and positively correlated with chemoresistance and short survival, which highlights their potentiality for targeted therapy. Therefore, we discovered a novel CCC surface marker regulated by a pathway that promotes chemoresistance, as well as a leading drug candidate to target this pathway.