Rapamycin downregulates thymidylate synthase and potentiates the activity of pemetrexed in non-small cell lung cancer

摘要: // Shigeru Kawabata 1,* , Chun-Te Chiang 2,* Junji Tsurutani 2 Hideaki Shiga 2,3 Matthew L. Arwood 1 Takefumi Komiya Joell J. Gills Regan M. Memmott and Phillip A. Dennis Department of Oncology, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA Oncology Branch, Center for Cancer Research, National Institute, Bethesda, 3 Current address: Otorhinolaryngology, Kanazawa University, Ishikawa, Japan * These authors contributed equally to this work Correspondence: Dennis, email: Keywords : Rapamycin, Pemetrexed, Drug synergy, mTOR, Thymidylate Synthase, Lung Received January 7, 2014 Accepted February 15, Published 16, Abstract Non-small cell lung cancer (NSCLC) accounts 80–85% cases, almost half newly diagnosed patients have metastatic disease. Pemetrexed is a widely used drug NSCLC inhibits several folate-dependent enzymes including thymidylate synthase (TS). Increased expression TS confers resistance pemetrexed in vitro predicts poor response pemetrexed. Rapamycin an mTOR inhibitor suppresses cap-dependent synthesis specific mRNA species. Here, we show that the combination rapamycin synergistically proliferation cells. Although as single agent induced TS, pretreatment with suppressed pemetrexed-induced expression. In vivo inhibited growth xenografts, which correlated decreased activity suppression The ability enhance efficacy prevent has implications design Phase I and/or II clinical trials inhibitors