Rapamycin Downregulates Thymidylate Synthase and Potentiates the Activity of Pemetrexed in Non-small Cell Lung Cancer

Overview

Journal Oncotarget

Specialty Oncology

Date 2014 Mar 25

PMID 24658085

Citations 20

Authors

Shigeru Kawabata

Chun-Te Chiang

Junji Tsurutani

Hideaki Shiga

Matthew L Arwood

Takefumi Komiya

Joell J Gills

Regan M Memmott

Phillip A Dennis

Affiliations

Soon will be listed here.

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.

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