Pancreatic Ductal Adenocarcinoma (PDAC) is the 3rd leading cause of cancer related death and has a five year survival rate below 8%. This poor prognosis is largely attributed to late diagnosis, which leaves clinicians to treat an advanced, chemoresistant disease. Gemcitabine based therapy is the standard of care for patients; however, in the majority of cases, patients exhibit tumor relapse and resistance. The overall goal of this research was to identify a mechanism of chemoresistance and develop a strategy to exploit it, in order to improve the efficacy of Gemcitabine (GEM). It was established that induction of GRP78, an endoplasmic reticulum chaperone protein, has a direct relationship with the GEM-resistant status of pancreatic cancer cell lines and tumors. Furthermore, it was found that GRP78 could be induced by GEM, itself, potentially inducing its own resistance mechanism. siRNA knockdown of GRP78 expression was able to reverse the GEM-resistant status of cell lines. Further, IT-139, a first in class, ruthenium based  compound, was used to target GRP78 induction and enhanced the efficacy of GEM in vitro and in vivo. Mechanistically, it was determined that IT-139 prevents the stress induction of GRP78, as well as downstream targets P-AKT and IRE1a. It was also determined that GRP78 induction may not be limited to GEM, and that DNA damaging agents also have the potential to induce the unfolded protein burden in cells, resulting in a subsequent induction of GRP78. Because GRP78 has been connected to poor prognosis across cancer types and treatments, it is possible that GRP78 targeting, via IT-139, can be used to improve the efficacy of chemotherapeutics in cancers beyond GEM therapy in PDAC.