Critical analysis of the potential for therapeutic targeting of mammalian target of rapamycin (mTOR) in gastric cancer

References

• Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.
   PubMed Web of Science ®Google Scholar
• Catalano V, Labianca R, Beretta GD, Gatta G, de Braud F, Van Cutsem E. Gastric cancer. Crit Rev Oncol Hematol. 2009;71(2):127–164.
   PubMed Web of Science ®Google Scholar
• Nashimoto A, Akazawa K, Isobe Y, et al. Gastric cancer treated in 2002 in Japan: 2009 annual report of the JGCA nationwide registry. Gastric Cancer. 2013;16(1):1–27.
   PubMed Web of Science ®Google Scholar
• Koizumi W, Narahara H, Hara T, et al. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 2008;9(3):215–221.
   PubMed Web of Science ®Google Scholar
• Narahara H, Iishi H, Imamura H, et al. Randomized phase III study comparing the efficacy and safety of irinotecan plus S-1 with S-1 alone as first-line treatment for advanced gastric cancer (study GC0301/ TOP-002). Gastric Cancer. 2011;14(1):72–80.
   Web of Science ®Google Scholar
• Koizumi W, Kim YH, Fujii M, et al; The JACCRO and KCSG Study Group. Addition of docetaxel to S-1 without platinum prolongs survival of patients with advanced gastric cancer: a randomized study (START). J Cancer Res Clin Oncol. 2014;140(2):319–328.
   PubMed Web of Science ®Google Scholar
• Ajani JA, Rodriguez W, Bodoky G, et al. Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. J Clin Oncol. 2010;28(9):1547–1553.
   PubMed Web of Science ®Google Scholar
• Ajani JA, Faust J, Ikeda K, et al. Phase I pharmacokinetic study of S-1 plus cisplatin in patients with advanced gastric carcinoma. J Clin Oncol. 2005;23(28):6957–6965.
   PubMed Web of Science ®Google Scholar
• Cunningham D, Starling N, Rao S, et al; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358(1):36–46.
   PubMed Web of Science ®Google Scholar
• Van Cutsem E, Moiseyenko VM, Tjulandin S, et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006;24(31):4991–4997.
   PubMed Web of Science ®Google Scholar
• Koizumi W, Nakayama N, Tanabe S, et al. A multicenter phase II study of combined chemotherapy with docetaxel, cisplatin, and S-1 in patients with unresectable or recurrent gastric cancer (KDOG 0601). Cancer Chemother Pharmacol. 2012;69(2):407–413.
   Web of Science ®Google Scholar
• Takeuchi K, Ito F. Receptor tyrosine kinases and targeted cancer therapeutics. Biol Pharm Bull. 2011;34(12):1774–1780.
   PubMed Web of Science ®Google Scholar
• Kim MA, Lee HS, Lee HE, Jeon YK, Yang HK, Kim WH. EGFR in gastric carcinomas: prognostic significance of protein overexpression and high gene copy number. Histopathology. 2008;52(6):738–746.
   PubMed Web of Science ®Google Scholar
• Begnami MD, Fukuda E, Fregnani JH, et al. Prognostic implications of altered human epidermal growth factor receptors (HERs) in gastric carcinomas: HER2 and HER3 are predictors of poor outcome. J Clin Oncol. 2011;29(22):3030–3036.
   PubMed Web of Science ®Google Scholar
• Jørgensen JT, Hersom M. HER2 as a prognostic marker in gastric cancer – a systematic analysis of data from the literature. J Cancer. 2012;3:137–144.
   PubMed Web of Science ®Google Scholar
• Hirashima Y, Yamada Y, Matsubara J, et al. Impact of vascular endothelial growth factor receptor 1, 2, and 3 expression on the outcome of patients with gastric cancer. Cancer Sci. 2009;100(2):310–315.
   PubMed Web of Science ®Google Scholar
• Mimori K, Fukagawa T, Kosaka Y, et al. Hematogenous metastasis in gastric cancer requires isolated tumor cells and expression of vascular endothelial growth factor receptor-1. Clin Cancer Res. 2008;14(9):2609–2616.
   Web of Science ®Google Scholar
• Ha SY, Lee J, Kang SY, et al. MET overexpression assessed by new interpretation method predicts gene amplification and poor survival in advanced gastric carcinomas. Mod Pathol. 2013;26(12):1632–1641.
   PubMed Web of Science ®Google Scholar
• Lee HE, Kim MA, Lee HS, et al. MET in gastric carcinomas: comparison between protein expression and gene copy number and impact on clinical outcome. Br J Cancer. 2012;107(2):325–333.
   PubMed Web of Science ®Google Scholar
• Bang YJ, Van Cutsem E, Feyereislova A, et al; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687–697.
   PubMed Web of Science ®Google Scholar
• Lordick F, Kang YK, Chung HC, et al; Arbeitsgemeinschaft Internistische Onkologie and EXPAND Investigators. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 2013;14(6):490–499.
   PubMed Web of Science ®Google Scholar
• Waddell T, Chau I, Cunningham D, et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol. 2013;14(6):481–489.
   PubMed Web of Science ®Google Scholar
• Bang YJ. A randomized, open-label, phase III study of lapatinib in combination with weekly paclitaxel versus weekly paclitaxel alone in the second-line treatment of HER2 amplified advanced gastric cancer in Asian populations: Tytan study. J Clin Oncol. 2013;31(Suppl 4): abstract 11.
   Web of Science ®Google Scholar
• Ohtsu A, Shah MA, Van Cutsem E, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011;29(30):3968–3976.
   PubMed Web of Science ®Google Scholar
• Van Cutsem E, de Haas S, Kang YK, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial. J Clin Oncol. 2012;30(17):2119–2127.
   PubMed Web of Science ®Google Scholar
• Fuchs CS, Tomasek J, Yong CJ, et al; REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383(9911):31–39.
   PubMed Web of Science ®Google Scholar
• Iveson T, Donehower RC, Davidenko I, et al. 6504 ORAL safety and efficacy of epirubicin, cisplatin, and capecitabine plus rilotumumab as first-line treatment for unresectable locally advanced or metastatic gastric or esophagogastric junction adenocarcinoma. Eur J Cancer. 2011;47(Suppl 1):S443.
   Google Scholar
• Shah MA, Wainberg ZA, Catenacci DV, et al. Phase II study evaluating 2 dosing schedules of oral foretinib (GSK1363089), cMET/VEGFR2 inhibitor, in patients with metastatic gastric cancer. PLoS One. 2013;8(3):e54014.
   PubMed Web of Science ®Google Scholar
• Sun W, Powell M, O’Dwyer PJ, Catalano P, Ansari RH, Benson AB. Phase II study of sorafenib in combination with docetaxel and cisplatin in the treatment of metastatic or advanced gastric and gastroesophageal junction adenocarcinoma: ECOG 5203. J Clin Oncol. 2010;28(18):2947–2951.
   PubMed Web of Science ®Google Scholar
• Bang YJ, Kang YK, Kang WK, et al. Phase II study of sunitinib as second-line treatment for advanced gastric cancer. Invest New Drugs. 2011;29(6):1449–1458.
   PubMed Web of Science ®Google Scholar
• Moehler M, Mueller A, Hartmann JT, et al; German Arbeitsgemeinschaft Internistische Onkologie (AIO). An open-label, multicentre biomarker-oriented AIO phase II trial of sunitinib for patients with chemo-refractory advanced gastric cancer. Eur J Cancer. 2011;47(10):1511–1520.
   PubMed Web of Science ®Google Scholar
• Fingar DC, Richardson CJ, Tee AR, Cheatham L, Tsou C, Blenis J. mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol. 2004;24(1):200–216.
   PubMed Web of Science ®Google Scholar
• Edinger AL, Thompson CB. Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake. Mol Biol Cell. 2002;13(7):2276–2288.
   PubMed Web of Science ®Google Scholar
• Al-Batran SE, Ducreux M, Ohtsu A. mTOR as a therapeutic target in patients with gastric cancer. Int J Cancer. 2012;130(3):491–496.
   PubMed Web of Science ®Google Scholar
• Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18(16):1926–1945.
   PubMed Web of Science ®Google Scholar
• Su B, Jacinto E. Mammalian TOR signaling to the AGC kinases. Crit Rev Biochem Mol Biol. 2011;46(6):527–547.
   Web of Science ®Google Scholar
• Hara K, Maruki Y, Long X, et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell. 2002;110(2):177–189.
   PubMed Web of Science ®Google Scholar
• Loewith R, Jacinto E, Wullschleger S, et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell. 2002;10(3):457–468.
   PubMed Web of Science ®Google Scholar
• Kim DH, Sarbassov DD, Ali SM, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell. 2002;110(2):163–175.
   PubMed Web of Science ®Google Scholar
• Wang L, Lawrence JC Jr, Sturgill TW, Harris TE. Mammalian target of rapamycin complex 1 (mTORC1) activity is associated with phosphorylation of raptor by mTOR. J Biol Chem. 2009;284(22):14693–14697.
   PubMed Web of Science ®Google Scholar
• Foster KG, Acosta-Jaquez HA, Romeo Y, et al. Regulation of mTOR complex 1 (mTORC1) by raptor Ser863 and multisite phosphorylation. J Biol Chem. 2010;285(1):80–94.
   PubMed Web of Science ®Google Scholar
• Janus A, Robak T, Smolewski P. The mammalian target of the rapamycin (mTOR) kinase pathway: its role in tumourigenesis and targeted antitumour therapy. Cell Mol Biol Lett. 2005;10(3):479–498.
   PubMed Web of Science ®Google Scholar
• Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 2006;6(9):729–734.
   PubMed Web of Science ®Google Scholar
• Sarbassov DD, Ali SM, Kim DH, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol. 2004;14(14):1296–1302.
   PubMed Web of Science ®Google Scholar
• Jacinto E, Loewith R, Schmidt A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004;6(11):1122–1128.
   PubMed Web of Science ®Google Scholar
• Wander SA, Hennessy BT, Slingerland JM. Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy. J Clin Invest. 2011;121(4):1231–1241.
   PubMed Web of Science ®Google Scholar
• Dowling RJ, Topisirovic I, Fonseca BD, Sonenberg N. Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochim Biophys Acta. 2010;1804(3):433–439.
   PubMed Web of Science ®Google Scholar
• Lorin S, Hamaï A, Mehrpour M, et al. Autophagy regulation and its role in cancer. Semin Cancer Biol. 2013;23(5):361–379.
   Web of Science ®Google Scholar
• Bachmann RA, Kim JH, Wu AL, Park IH, Chen J. A nuclear transport signal in mammalian target of rapamycin is critical for its cytoplasmic signaling to S6 kinase 1. J Biol Chem. 2006;281(11):7357–7363.
   Web of Science ®Google Scholar
• Rosner M, Hengstschläger M. Cytoplasmic and nuclear distribution of the protein complexes mTORC1 and mTORC2: rapamycin triggers dephosphorylation and delocalization of the mTORC2 components rictor and sin1. Hum Mol Genet. 2008;17(19):2934–2948.
   PubMed Web of Science ®Google Scholar
• Murayama T, Inokuchi M, Takagi Y, et al. Relation between outcomes and localisation of p-mTOR expression in gastric cancer. Br J Cancer. 2009;100(5):782–788.
   PubMed Web of Science ®Google Scholar
• Yu G, Wang J, Chen Y, et al. Overexpression of phosphorylated mammalian target of rapamycin predicts lymph node metastasis and prognosis of chinese patients with gastric cancer. Clin Cancer Res. 2009;15(5):1821–1829.
   Web of Science ®Google Scholar
• Xu DZ, Geng QR, Tian Y, et al. Activated mammalian target of rapamycin is a potential therapeutic target in gastric cancer. BMC Cancer. 2010;10:536.
   Web of Science ®Google Scholar
• An JY, Kim KM, Choi MG, et al. Prognostic role of p-mTOR expression in cancer tissues and metastatic lymph nodes in pT2b gastric cancer. Int J Cancer. 2010;126(12):2904–2913.
   Web of Science ®Google Scholar
• Lang SA, Gaumann A, Koehl GE, et al. Mammalian target of rapamycin is activated in human gastric cancer and serves as a target for therapy in an experimental model. Int J Cancer. 2007;120(8):1803–1810.
   PubMed Web of Science ®Google Scholar
• Feng W, Brown RE, Trung CD, et al. Morphoproteomic profile of mTOR, Ras/Raf kinase/ERK, and NF-kappaB pathways in human gastric adenocarcinoma. Ann Clin Lab Sci. 2008;38(3):195–209.
   Web of Science ®Google Scholar
• Li M, Sun H, Song L, Gao X, Chang W, Qin X. Immunohistochemical expression of mTOR negatively correlates with PTEN expression in gastric carcinoma. Oncol Lett. 2012;4(6):1213–1218.
   Web of Science ®Google Scholar
• Xiao L, Wang YC, Li WS, Du Y. The role of mTOR and phospho-p70S6K in pathogenesis and progression of gastric carcinomas: an immunohistochemical study on tissue microarray. J Exp Clin Cancer Res. 2009;28:152.
   PubMed Web of Science ®Google Scholar
• Hashimoto I, Koizumi K, Tatematsu M, et al. Blocking on the CXCR4/mTOR signalling pathway induces the anti-metastatic properties and autophagic cell death in peritoneal disseminated gastric cancer cells. Eur J Cancer. 2008;44(7):1022–1029.
   PubMed Web of Science ®Google Scholar
• Lang SA, Hackl C, Moser C, et al. Implication of RICTOR in the mTOR inhibitor-mediated induction of insulin-like growth factor-I receptor (IGF-IR) and human epidermal growth factor receptor-2 (Her2) expression in gastrointestinal cancer cells. Biochim Biophys Acta. 2010;1803(4):435–442.
   Web of Science ®Google Scholar
• Cejka D, Preusser M, Woehrer A, et al. Everolimus (RAD001) and anti-angiogenic cyclophosphamide show long-term control of gastric cancer growth in vivo. Cancer Biol Ther. 2008;7(9):1377–1385.
   PubMed Web of Science ®Google Scholar
• Fuereder T, Jaeger-Lansky A, Hoeflmayer D, et al. mTOR inhibition by everolimus counteracts VEGF induction by sunitinib and improves anti-tumor activity against gastric cancer in vivo. Cancer Lett. 2010;296(2):249–256.
   Web of Science ®Google Scholar
• Shigematsu H, Yoshida K, Sanada Y, et al. Rapamycin enhances chemotherapy-induced cytotoxicity by inhibiting the expressions of TS and ERK in gastric cancer cells. Int J Cancer. 2010;126(11):2716–2725.
   Web of Science ®Google Scholar
• Thiem S, Pierce TP, Palmieri M, et al. mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice. J Clin Invest. 2013;123(2):767–781.
   PubMed Web of Science ®Google Scholar
• Taguchi F, Kodera Y, Katanasaka Y, Yanagihara K, Tamura T, Koizumi F. Efficacy of RAD001 (everolimus) against advanced gastric cancer with peritoneal dissemination. Invest New Drugs. 2011;29(6):1198–1205.
   PubMed Web of Science ®Google Scholar
• Nishi T, Iwasaki K, Ohashi N, et al. Phosphorylation of 4E-BP1 predicts sensitivity to everolimus in gastric cancer cells. Cancer Lett. 2013; 331(2):220–229.
   Web of Science ®Google Scholar
• Matsuzaki T, Yashiro M, Kaizaki R, et al. Synergistic antiproliferative effect of mTOR inhibitors in combination with 5-fluorouracil in scirrhous gastric cancer. Cancer Sci. 2009;100(12):2402–2410.
   PubMed Web of Science ®Google Scholar
• Lee KH, Hur HS, Im SA, et al. RAD001 shows activity against gastric cancer cells and overcomes 5-FU resistance by downregulating thymidylate synthase. Cancer Lett. 2010;299(1):22–28.
   PubMed Web of Science ®Google Scholar
• Tomioka H, Mukohara T, Kataoka Y, et al. Inhibition of the mTOR/S6K signal is necessary to enhance fluorouracil-induced apoptosis in gastric cancer cells with HER2 amplification. Int J Oncol. 2012;41(2):551–558.
   Web of Science ®Google Scholar
• Ji D, Zhang Z, Cheng L, et al. The combination of RAD001 and MK-2206 exerts synergistic cytotoxic effects against PTEN mutant gastric cancer cells: involvement of MAPK-dependent autophagic, but not apoptotic cell death pathway PLoS One. 2014;9(1):e85116.
   PubMed Web of Science ®Google Scholar
• Okamoto I, Doi T, Ohtsu A, et al. Phase I clinical and pharmacokinetic study of RAD001 (everolimus) administered daily to Japanese patients with advanced solid tumors. Jpn J Clin Oncol. 2010;40(1):17–23.
   PubMed Web of Science ®Google Scholar
• Werner D, Atmaca A, Pauligk C, Pustowka A, Jäger E, Al-Batran SE. Phase I study of everolimus and mitomycin C for patients with metastatic esophagogastric adenocarcinoma. Cancer Med. 2013;2(3):325–333.
   PubMed Web of Science ®Google Scholar
• Doi T, Muro K, Boku N, et al. Multicenter phase II study of everolimus in patients with previously treated metastatic gastric cancer. J Clin Oncol. 2010;28(11):1904–1910.
   PubMed Web of Science ®Google Scholar
• Yoon DH, Ryu MH, Park YS, et al. Phase II study of everolimus with biomarker exploration in patients with advanced gastric cancer refractory to chemotherapy including fluoropyrimidine and platinum. Br J Cancer. 2012;106(6):1039–1044.
   PubMed Web of Science ®Google Scholar
• Lim T, Lee J, Lee DJ, et al. Phase I trial of capecitabine plus everolimus (RAD001) in patients with previously treated metastatic gastric cancer. Cancer Chemother Pharmacol. 2011;68(1):255–262.
   PubMed Web of Science ®Google Scholar
• Lee SJ, Lee J, Lee J, et al. Phase II trial of capecitabine and everolimus (RAD001) combination in refractory gastric cancer patients. Invest New Drugs. 2013;31(6):1580–1586.
   PubMed Web of Science ®Google Scholar
• Ohtsu A, Ajani JA, Bai YX, et al. Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study. J Clin Oncol. 2013;31(31):3935–3943.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Escudier B, Oudard S, et al; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372(9637):449–456.
   PubMed Web of Science ®Google Scholar
• Demetri GD, Chawla SP, Ray-Coquard I, et al. Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy. J Clin Oncol. 2013;31(19):2485–2492.
   PubMed Web of Science ®Google Scholar
• Wolpin BM, Hezel AF, Abrams T, et al. Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer. J Clin Oncol. 2009;27(2):193–198.
   PubMed Web of Science ®Google Scholar
• Javle MM, Shroff RT, Xiong H, et al. Inhibition of the mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: results of two phase II studies. BMC Cancer. 2010;10:368.
   PubMed Web of Science ®Google Scholar
• Tarhini A, Kotsakis A, Gooding W, et al. Phase II study of everolimus (RAD001) in previously treated small cell lung cancer. Clin Cancer Res. 2010;16(23):5900–5907.
   PubMed Web of Science ®Google Scholar
• Zhu AX, Abrams TA, Miksad R, et al. Phase 1/2 study of everolimus in advanced hepatocellular carcinoma. Cancer. 2011;117(22):5094–5102.
   PubMed Web of Science ®Google Scholar
• Hironaka S, Ueda S, Yasui H, et al. Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol. 2013;31(35):4438–4444.
   PubMed Web of Science ®Google Scholar
• A Randomized, Double Blind Study Evaluating Paclitaxel With and Without RAD001 in Patients With Gastric Carcinoma After Prior Chemotherapy (AIO-STO-0111). Avaliable from: http://clinicaltrials.gov/show/NCT01248403.
   Google Scholar
• Motzer RJ, Nosov D, Eisen T, et al. Record-3: Phase II randomized trial comparing sequential first-line everolimus (EVE) and second-line sunitinib (SUN) versus first-line SUN and second-line EVE in patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2013;31(Suppl):abstract 4504.
   Web of Science ®Google Scholar