Reference Detail

Ref Type Journal Article
PMID (24658085)
Authors Kawabata S, Chiang CT, Tsurutani J, Shiga H, Arwood ML, Komiya T, Gills JJ, Memmott RM, Dennis PA
Title Rapamycin downregulates thymidylate synthase and potentiates the activity of pemetrexed in non-small cell lung cancer.
Journal Oncotarget
Vol 5
Issue 4
Date 2014 Feb 28
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown lung non-small cell carcinoma not applicable Pemetrexed + Sirolimus Phase Ib/II Actionable In a Phase Ib/II trial, Rapamune (sirolimus) in combination with Alimta (pemetrexed) demonstrated safety and some efficacy in treating patients with NSCLC (PMID: 24658085). 24658085