Abstract 4038: Investigating the effect of glucose-regulated protein 78 (GRP78) inhibition in pancreatic cancer chemoresistance.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related deaths in the United States with a 5-year survival rate of 6%. Current therapeutic regimens have done little to halt the progression of this disease. This demonstrates an urgent need for novel therapeutic strategies which address the mechanisms underlying the tumor cells’ ability to develop resistance to drug treatment. Increased expression of GRP78, a member of the Hsp70 protein family, is associated with poor prognosis in a number of human cancers. This prompted us to explore the role of GRP78 expression in pancreatic tumorigenesis.

Our data show that while no GRP78 expression was observed in the ducts of wild-type pancreata, GRP78 expression is significantly increased in the ductal cells of PDACs in our murine models. Moreover, this upregulated GRP78 expression, especially its membrane-associated form, corresponded to P-AKT activation. Our previous results showed that increased P-AKT signaling is significantly associated with distinct pancreatic cancer patient subgroups with more aggressive disease progression. Taken together, these data raised the question of whether GRP78 is essential for pancreatic chemoresistance.

GRP78 expression was inhibited in several gemcitabine resistant PDAC cell lines using siRNA. GRP78 knockdown produced no measurable levels of cell death in any cell lines tested. Likewise, treatment with gemcitabine alone produced very little cell death. However, gemcitabine treatment in cells with GRP78 knockdown showed significantly increased cell death. Examination of cells treated with GRP78 siRNA showed decreased P-AKT activation. These data suggest GRP78 could serve as a potential therapeutic target for chemoresistant pancreatic cancers which show PI3K/AKT pathway activation.

Citation Format: Katherine Richards, Ellen Gunn, Reginald Hill. Investigating the effect of glucose-regulated protein 78 (GRP78) inhibition in pancreatic cancer chemoresistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4038. doi:10.1158/1538-7445.AM2013-4038