In this study, we carried out a proteomics analysis of cell and extracellular vesicles from nontumor and pancreatic adenocarcinoma (PDAC) tumor cells. We found out that PDAC cells preferentially excrete some proteins with preference for certain amino acids including isoleucine and histidine. Through in vitro and in vivo results, these amino acids demonstrate selective toxicity to PDAC cells and we subsequently identified XRN1 as a potential target of the amino acids.