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

Shigeru Kawabata, Chun Te Chiang, Junji Tsurutani, Hideaki Shiga, Matthew L. Arwood, Takefumi Komiya, Joell J. Gills, Regan M. Memmott, Phillip A. Dennis

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1062-1070
Number of pages9
JournalOncotarget
Volume5
Issue number4
DOIs
StatePublished - 2014

Keywords

  • Drug synergy
  • Lung cancer
  • Pemetrexed
  • Rapamycin
  • Thymidylate synthase
  • mTOR

ASJC Scopus subject areas

  • Oncology

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