Rapamycin downregulates thymidylate synthase and potentiates the activity of pemetrexed in non-small cell lung cancer
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Shigeru Kawabata1,*, Chun-Te Chiang2,*, Junji Tsurutani2, Hideaki Shiga2,3, Matthew L. Arwood1, Takefumi Komiya2, Joell J. Gills1, Regan M. Memmott1, and Phillip A. Dennis1
1 Department of Oncology, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA
2 Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
3 Current address: Department of Otorhinolaryngology, Kanazawa Medical University, Ishikawa, Japan
* These authors contributed equally to this work
Phillip A. Dennis, email:
Keywords: Rapamycin, Pemetrexed, Drug synergy, mTOR, Thymidylate Synthase, Lung Cancer
Received: January 7, 2014 Accepted: February 15, 2014 Published: February 16, 2014
Non-small cell lung cancer (NSCLC) accounts for 80–85% of lung cancer cases, and almost half of newly diagnosed patients have metastatic disease. Pemetrexed is a widely used drug for NSCLC and inhibits several folate-dependent enzymes including thymidylate synthase (TS). Increased expression of TS confers resistance to pemetrexed in vitro and predicts poor response to pemetrexed. Rapamycin is an mTOR inhibitor and suppresses cap-dependent synthesis of specific mRNA species. Here, we show that the combination of rapamycin and pemetrexed synergistically inhibits proliferation of NSCLC cells. Although pemetrexed as a single agent induced TS, pretreatment with rapamycin suppressed pemetrexed-induced TS expression. In vivo, the combination of rapamycin and pemetrexed inhibited growth of NSCLC xenografts, which correlated with decreased mTOR activity and suppression of pemetrexed-induced TS expression. The ability of rapamycin to enhance the efficacy of pemetrexed and prevent TS expression has implications for the design of Phase I and/or Phase II NSCLC clinical trials with mTOR inhibitors in combination with pemetrexed.
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