Pancreatic ductal adenocarcinoma (PDAC) remains a lethal, RAS-driven cancer with the incidence increasing 60% over the last decade. Current chemotherapy does not produce an extension in survival and results in drug resistance. Thymidylate synthase (TYMS), an enzyme involved in DNA synthesis and repair, plays a direct role in promoting tumorigenesis. High levels of TYMS have been associated with poor clinical outcomes in many cancers. Zajac-Kaye Laboratory has shown that overexpression of TYMS cooperates with mutant KRAS to accelerate tumor progression of PDAC. The main goal of this project will be to study the effect of a new therapeutic approach in a PDAC xenograft model. We will determine the antitumoral effect of a TYMS inhibitor recently identified in the Zajac-Kaye Laboratory alone and combined separately with Temsirolimus or TAK-228, which are both KRAS/P13K/mTOR pathway inhibitors.