title: Synergistic antitumor effect of S-1 and HER2-targeting agents in gastric cancer with HER2 amplification.
abstract: Amplification of human epidermal growth factor receptor 2 (HER2) has been detected in 20% to 30% of gastric cancers and is associated with a poor outcome. Combination therapies with HER2-targeting agents and cytotoxic agents are considered a potential therapeutic option for gastric cancer with HER2 amplification. We have now investigated the effects of combination treatment with the oral fluoropyrimidine S-1 and the HER2-targeting agents lapatinib or trastuzumab in gastric cancer cells with or without HER2 amplification. We used 5-fluorouracil (5FU) instead of S-1 for in vitro experiments, given that tegafur, a component of S-1, is metabolized to 5FU in the liver. The combination of 5FU and HER2-targeting agents synergistically inhibited cell proliferation and exhibited an enhanced proapoptotic effect in gastric cancer cells with HER2 amplification, but not in those without it. Lapatinib or trastuzumab also induced downregulation of thymidylate synthase (TS) expression and activity only in cells with HER2 amplification. The combination of 5FU and TS depletion by RNA interference also exhibited an enhanced proapoptotic effect in cells with HER2 amplification. These observations thus suggest that lapatinib-induced or trastuzumab-induced downregulation of TS is responsible, at least in part, for the synergistic antitumor effect of combined treatment with 5FU and HER2-targeting agents. The antitumor effect of the combination of S-1 and HER2-targeting agents in vivo was also greater than that of either drug alone. Our preclinical findings thus indicate that the combination of S-1 and HER2-targeting agents is a promising treatment option for gastric cancer with HER2 amplification.
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Tanizaki
authors.forename: Isamu
authors.initials: I
authors.lastname: Okamoto
authors.forename: Ken
authors.initials: K
authors.lastname: Takezawa
authors.forename: Sayaka
authors.initials: S
authors.lastname: Tsukioka
authors.forename: Junji
authors.initials: J
authors.lastname: Uchida
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kiniwa
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fukuoka
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004338:Drug Combinations; D016503:Drug Delivery Systems; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage; D005784:Gene Amplification; D006801:Humans; D000077341:Lapatinib; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010094:Oxonic Acid / Q000008:administration & dosage*; D011799:Quinazolines / Q000008:administration & dosage*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005641:Tegafur / Q000008:administration & dosage*; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D004338:Drug Combinations; D005472:Fluorouracil; D000077341:Lapatinib; D010094:Oxonic Acid; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D005641:Tegafur; D000068878:Trastuzumab; C079198:S 1 (combination)