OSI-027 inhibits pancreatic ductal adenocarcinoma cell proliferation and enhances the therapeutic effect of gemcitabine both in vitro and in vivo

// Xiao Zhi 1, * , Wei Chen 1, * , Fei Xue 1 , Chao Liang 1 , Bryan Wei Chen 1 , Yue Zhou 1 , Liang Wen 1 , Liqiang Hu 1 , Jian Shen 1 , Xueli Bai 1, 2 , Tingbo Liang 1, 2, 3 1 Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, P.R.China 2 Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P.R.China 3 Collaborative Innovation Center for Cancer Medicine, Zhejiang University, Hangzhou, P.R.China * These authors have contributed equally to this work Correspondence to: Tingbo Liang, e-mail: liangtingbo@zju.edu.cn Xueli Bai, e-mail: shirleybai57@hotmail.com Keywords: PDAC, mTOR, OSI-027, gemcitabine, multidrug resistance Received: April 06, 2015      Accepted: July 10, 2015      Published: July 21, 2015 ABSTRACT 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.