Targeting EGFR improves the chemoprevention effects of HDAC inhibitors for pancreatic cancer.

A112

Pancreatic cancer is a lethal disease because it is difficult to detect and treat. However, pancreatic cancer progresses over many years, which offers the opportunity for prevention. Over 90% of pancreatic tumors have a point mutation in K-Ras at codon, which leads to activation of the Ras, epidermal growth factor receptor (EGFR), and vascular endothelial cell growth factor receptor (VEGFR) signaling pathways. Pancreatic cancer is an epigenetic disease with profound alterations in gene methylation. In contrast, histone deacetylase inhibitors (HDACi) can restore epigenetic alterations in gene functioning. This study investigated whether the combination of the EGFR/ VEGFR inhibitor ZD6474 and the HDACi, Trichostatin A (TSA) was more protective in human pancreatic cancer cells than higher doses of these agents alone. PK-9 and BxPC-3 cells were treated with IC50 concentrations of ZD6474 and TSA for 72 hours for measurement of cell survival and apoptosis. Treating the pancreatic cancer cells with ZD6474 in combination with TSA decreased survival and induced apoptosis in a synergistic manner. The combination was associated with decreased activation of EGFR, ERK1/2, and Akt survival signaling. The synergistic apoptotic effect was associated with an increased in cleaved poly (ADP-ribose)polymerase (PARP). These findings with HDACi combined with agents that target EGFR may represent a novel strategy for preventing pancreatic cancer in a high-risk population.