title: Rapamycin downregulates thymidylate synthase and potentiates the activity of pemetrexed in non-small cell lung cancer.
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.
authors.affiliation: Department of Oncology, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kawabata
authors.forename: Chun-Te
authors.initials: CT
authors.lastname: Chiang
authors.forename: Junji
authors.initials: J
authors.lastname: Tsurutani
authors.forename: Hideaki
authors.initials: H
authors.lastname: Shiga
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Arwood
authors.forename: Takefumi
authors.initials: T
authors.lastname: Komiya
authors.forename: Joell J
authors.initials: JJ
authors.lastname: Gills
authors.forename: Regan M
authors.initials: RM
authors.lastname: Memmott
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Dennis
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D004357:Drug Synergism; D005260:Female; D005971:Glutamates / Q000008:administration & dosage / Q000494:pharmacology*; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D000068437:Pemetrexed; D020123:Sirolimus / Q000494:pharmacology*; D013940:Thymidylate Synthase / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D013940:Thymidylate Synthase; D020123:Sirolimus