Genetic alterations activating K-RAS and PI3K/AKT signaling are also known to induce the activity of mTOR
kinase through
TORC1 and
TORC2 complexes in human pancreatic ductal
adenocarcinoma (PDAC). Here, we determined the effects of the dual PI3K and mTOR inhibitor,
NVP-BEZ235 (
BEZ235), and the pan-
histone deacetylase inhibitor panobinostat (PS) against human PDAC cells. Treatment with
BEZ235 or PS inhibited cell cycle progression with induction of the cell cycle inhibitory
proteins, p21waf1 and p27kip1.
BEZ235 and PS also dose dependently induced loss of cell viability of the cultured PDAC cells, associated with depletion of phosphorylated (p) AKT, as well as of the
TORC1 substrates 4EBP1 and p70S6
kinase. While inhibiting p-AKT, treatment with PS induced the levels of the
pro-apoptotic proteins BIM and BAK. Co-treatment with
BEZ235 and PS synergistically induced apoptosis of the cultured PDAC cells. This was accompanied by marked attenuation of the levels of p-AKT and Bcl-xL but induction of BIM. Although in vivo treatment with
BEZ235 or PS reduced
tumor growth, co-treatment with
BEZ235 and PS was significantly more effective in controlling the xenograft growth of Panc1 PDAC cells in the nude mice. Furthermore, co-treatment with
BEZ235 and PS more effectively blocked
tumor growth of primary PDAC heterotransplants (possessing K-RAS mutation and AKT2 amplification) subcutaneously implanted in the nude mice than each agent alone. These findings demonstrate superior activity and support further in vivo evaluation of combined treatment with
BEZ235 and PS against PDAC that possess heightened activity of RAS-RAF-ERK1/2 and PI3K-AKT-mTOR pathways.