Abstract 1688: Overcoming drug resistance to gemcitabine in pancreas cancer cells by targeting activated PI3K/mTOR pathway

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Pancreas cancer is one of the most difficult neoplasms to treat curatively and 5-year survival rate is only 5%. Gemcitabine, a difluorinated deoxycitidine, has been first reported to improve pancreas cancer both response rate and median overall survival of patients with pancreas cancer. Treatment with combination of gemcitabine and erlotinib was reported to prolong survival compared with gemcitabine alone against pancreas ductal adenocarcinoma, but its benefit is modest. Further development of potent combination therapeutics with gemcitabine should be very useful for treatment of pancreas cancer. In our present study, we examined whether the cytotoxic effect of gemcitabine could be potentiated when combined with other anticancer drugs including molecular targeted drugs and cytotoxic anticancer agents, and also whether such combination could overcome drug resistance to gemcitabine. We observed following findings [1]We first screened various anticancer agents that could synergistically potentiate cytotoxic effect of gemcitabine against pancreas cancer cell lines in culture, and observed that mTOR inhibitors, such as rapamycin, everolimus and AZD8055, synergistically enhanced the anti-proliferative effect of gemcitabine. [2] PI3K/mTOR/S6K-driven signaling pathway for de novo pyrimidine biosynthesis was markedly blocked when combined with gemcitabine and mTOR inhibitors. [3] We also observed that mTOR/S6K-driven de novo pyrimidine synthetic pathway was markedly activated in drug-resistant cancer cells as compared to their parental cell line. [4] Immunohistochemical analysis of clinical samples derived from resected pancreas tumors showed that mTOR was highly expressed in progressive pancreas cancer. Combination of gemcitabine and drugs targeting mTOR-driven signaling pathway will further provide potent therapeutics against both gemcitabine-sensitive and -resistant pancreas cancer. Furthermore, personalized therapeutics against pancreas cancer patients by this combination will be discussed based on expression levels of activated PI3K/mTOR/S6K in tumors. Citation Format: Yuichi Murakami, Ai Shinoda, Kosuke Watari, Hiroshi Nabeshima, Akihiko Kawahara, Daisuke Nagayama, Yoshiki Naito, Koichi Higaki, Masako Inoue, Michihiko Kuwano, Mayumi Ono. Overcoming drug resistance to gemcitabine in pancreas cancer cells by targeting activated PI3K/mTOR pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1688. doi:10.1158/1538-7445.AM2014-1688