Extracellular Signal-Regulated Kinase Inhibitor SCH772984 Augments the Anti-Cancer Effects of Gemcitabine in Nanoparticle Form in Pancreatic Cancer Models.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a poor response to the limited treatment options currently available. Hence, there is a need to identify new agents that could enhance the efficacy of existing treatments. This study investigated a combination therapy using gemcitabine (GEM) and SCH772984, an extracellular signal-regulated kinase (ERK) inhibitor, in both free form and nanoparticle-encapsulated form for PDAC treatment. Cell viability and Matrigel growth assays were used to determine the anti-proliferative and cytotoxic effects of GEM and SCH772984 on PDAC cells. Additionally, western blotting was used to determine the degree to which SCH772984 engaged ERK in PDAC cells. Lastly, immunohistochemistry and hematoxylin and eosin (H&E) staining were used to determine how GEM and SCH772984 affected expression of Ki-67 cell proliferation marker in PDX (patient derived xenograft) PDAC tissues. PDAC cell lines (MIA PaCa-2 and PANC-1) treated with the combination of free GEM and SCH772984 showed reduction in cell viability compared to cells treated with free GEM or SCH772984 administered as a single agent. Encapsulated forms of GEM and SCH772984 caused a greater reduction in cell viability than the free forms. Interestingly, co-administration of GEM and SCH772984 in separate nanoparticle (NP) systems exhibited the highest reduction in cell viability. Western blotting analysis confirmed ERK signaling was inhibited by both free and encapsulated SCH772984. Importantly, GEM did not interfere with the inhibitory effect of SCH772984 on phosphorylated ERK (pERK). Collectively, our studies suggest that combination therapy with GEM and SCH772984 effectively reduced PDAC cell viability and growth, and co-administration of NP encapsulated GEM and SCH772984 in separate NP systems is an effective treatment strategy for PDAC.