A targetable pathway to eliminate TRA-1-60+ /TRA-1-81+ chemoresistant cancer cells

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. Further- more, 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.