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5-fluorouracil (5-FU) , one of the first-line chemotherapeutic agents for the treatment of gastrointestinal malignancies, has shown limited efficacy. The expression of thymidylate synthase (TYMS) has been reported to be associated with the resistance to 5-FU. Here, we demonstrate that the enhanced HSP90 function and subsequent activation of Src induce expression of TYMS and acquired resistance to 5-FU in colon cancer. We show that the persistent 5-FU treatment granted 5-FU-sensitive HCT116doi:10.18632/oncotarget.5327 pmid:26416450 pmcid:PMC4741717 fatcat:7pehysvgg5chlattlgnnxhbx2q