A mechanism how mTOR inhibitor potentiate the effect of gemcitabine against pancreatic cancer

• Project/Area Number: 15K18923
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Medical pharmacy
• Research Institution: Kyushu University
• Principal Investigator: Murakami Yuichi 九州大学, 薬学研究院, 共同研究員 (60464385)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: mTOR / Gemcitabine

Outline of Final Research Achievements

Gemcitabine, a difluorinated deoxy cytidine analogue, shows clinical activity against various human solid tumors, including pancreas. Clinical application of the gemcitabine-base adjuvant therapy has improved progression-free survival of patients with pancreas cancer. Many clinical trials for gemcitabine-based chemotherapy with various drugs has been applied to patients with pancreas cancer. However, its benefit is modest.
In this study, we screened anticancer agents that can potentiate gemcitabine against human pancreatic cancer cells. We found that combination of mTOR inhibitor and GEM synergistically inhibit cell growth in pancreatic cancer cells. We also elucidated mechanism how mTOR inhibitors can augment the cytotoxic effect of gemcitabine. Inhibitor of mTOR induced CDA mRNA expression via stabilization of CDA mRNA.
Therefore, mTOR inhibitor might potentiate the therapeutic efficacy of gemcitabine through modification of nucleoside metabolism in pancreatic cancer cells.

Research Products

• [Journal Article] Breast cancer resistance to antiestrogens is enhanced by increased ER degradation and ERBB2 expression (2017)
  • Author(s): Tomohiro Shibata, Kosuke Watari, Hiroto Izumi, Akihiko Kawahara, Satoshi Hattori, Chihiro Fukumitsu, Yuichi Murakami, Ryuji Takahashi, Uhi Toh, Ken-ichi Ito, Shigehiro Ohdo, Maki Tanaka, Masayoshi Kage, Michihiko Kuwano, Mayumi Ono
  • Journal Title: Cancer Research Volume: 77 Issue: 2 Pages: 545-556
  • DOI: 10.1158/0008-5472.can-16-1593
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Overcoming drug resistance to receptor tyrosine kinase inhibitors: Learning from lung cancer. (2016)
  • Author(s): Kuwano M, Sonoda K, Murakami Y, Watari K, Ono M.
  • Journal Title: Pharmacol Ther Volume: 161 Pages: 97-110
  • DOI: 10.1016/j.pharmthera.2016.03.002
  • Peer Reviewed
• [Journal Article] Phosphorylation of mTOR Ser2481 is a key target limiting the efficacy of rapalogs for treating hepatocellular carcinoma. (2016)
  • Author(s): Watari K, Nishitani A, Shibata T, Noda M, Kawahara A, Akiba J, Murakami Y, Yano H, Kuwano M, Ono M.
  • Journal Title: Oncotarget Volume: 7 Issue: 30 Pages: 47403-47417
  • DOI: 10.18632/oncotarget.10161
  • Peer Reviewed
• [Presentation] ゲムシタビンとmTOR阻害剤の併用による相乗的な膵癌の増殖抑制効果のメカニズム (2015)
  • Author(s): 村上雄一, 渡公佑, 柴田智博, 河原明彦, 鹿毛政義, 桑野信彦, 小野眞弓
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-10-08
• [Remarks]
  • URL: http://shuyo.phar.kyushu-u.ac.jp/