Work

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

Year: 2014

Type: article

Abstract: // Shigeru Kawabata 1,* , Chun-Te Chiang 2,* , Junji Tsurutani 2 , Hideaki Shiga 2,3 , Matthew L. Arwood 1 , Takefumi Komiya 2 , Joell J. Gills 1 , Regan M. Memmott 1 , and Phillip A. Dennis 1 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 Correspondence: 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 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.1760