osi-027 and Carcinoma--Pancreatic-Ductal

Despite its relative rarity, pancreatic ductal adenocarcinoma (PDAC) accounts for a large percentage of cancer deaths. In this study, we investigated the in vitro efficacy of OSI-027, a selective inhibitor of mammalian target of rapamycin complex 1 (mTORC1) and mTORC2, to treat PDAC cell lines alone, and in combination with gemcitabine (GEM). Similarly, we tested the efficacy of these two compounds in a xenograft mouse model of PDAC. OSI-027 significantly arrested cell cycle in G0/G1 phase, inhibited the proliferation of Panc-1, BxPC-3, and CFPAC-1 cells, and downregulated mTORC1, mTORC2, phospho-Akt, phospho-p70S6K, phospho-4E-BP1, cyclin D1, and cyclin-dependent kinase 4 (CDK4) in these cells. Moreover, OSI-027 also downregulated multidrug resistance (MDR)-1, which has been implicated in chemotherapy resistance in PDAC cells and enhanced apoptosis induced by GEM in the three PDAC cell lines. When combined, OSI-027 with GEM showed synergistic cytotoxic effects both in vitro and in vivo. This is the first evidence of the efficacy of OSI-027 in PDAC and may provide the groundwork for a new clinical PDAC therapy.

Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Pancreatic Ductal; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cell Survival; Deoxycytidine; Dose-Response Relationship, Drug; Drug Synergism; Gemcitabine; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Inhibitory Concentration 50; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice, Inbred BALB C; Mice, Nude; Multiprotein Complexes; Pancreatic Neoplasms; Protein Kinase Inhibitors; RNA Interference; Signal Transduction; Time Factors; TOR Serine-Threonine Kinases; Transfection; Triazines; Tumor Burden; Xenograft Model Antitumor Assays