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Keywords:

  • everolimus;
  • gastric adenocarcinoma;
  • gastric cancer;
  • mTOR;
  • mTOR inhibitors

Abstract

  1. Top of page
  2. Abstract
  3. The mTOR pathway
  4. Discussion
  5. Acknowledgements
  6. References

The poor long-term outcomes associated with current chemotherapy treatment of patients with advanced gastric cancer suggest a need for novel targeted agents that may confer a better survival benefit. Evidence of mammalian target of rapamycin (mTOR) activation has been demonstrated in patient-derived gastric cancer cells and tumors. This review explores the relevance of the mTOR pathway to gastric cancer pathogenesis and its potential as a therapeutic target in patients with gastric cancer as well as presenting the first available clinical data on mTOR inhibitors in this disease setting. Preclinical data suggest that suppression of the mTOR pathway inhibited the proliferation of gastric cancer cells and delayed tumor progression in in vitro and animal models. In the clinical setting, the mTOR inhibitor everolimus has been active and well tolerated in phase I/II studies of patients with chemotherapy-refractory metastatic gastric cancer. Based on these promising results, everolimus currently is being investigated as a monotherapy or in combination with chemotherapeutic agents in ongoing phase II/III clinical studies.

Gastric cancer is the fourth most common cancer worldwide, with 640,556 new cases among men and 349,042 new cases among women annually, and it is the second most common cause of cancer death, with ∼738,069 deaths annually worldwide.1 Current management of gastric cancer is based on surgical resection of the primary tumor.2 Although surgical resection can be curative for patients with earlier stages of disease, 60% of patients in the Western hemisphere eventually relapse.3 Furthermore, most patients with gastric cancer commonly present with advanced unresectable disease. For patients with advanced disease or for those developing recurrent disease after surgery, evidence supports the use of chemotherapy to prolong survival and maintain quality of life.2, 3

At present there is no globally accepted standard chemotherapeutic regimen for the treatment of patients with gastric cancer.2 Combination chemotherapy regimens, including 5-fluorouracil (5-FU), taxanes, and platinum derivatives have been shown to prolong median overall survival in patients with advanced gastric cancer, although the duration of survival is usually less than 1 year,4–9 except for some trial results in Japanese patients.10–13 These poor long-term outcomes associated with chemotherapy treatments suggest a need for novel targeted agents that may confer a better survival benefit in patients with advanced gastric cancer. Targets currently under investigation include the mammalian target of rapamycin (mTOR) and human epidermal growth factor receptor-2 (HER2), which engage multiple downstream signaling pathways including the phosphoinositol-3 kinase (PI3K)/Akt/mTOR pathway. Both mTOR and HER2 are dysregulated in many cancers, including gastric cancer,14, 15 and may represent relevant therapeutic targets in patients with this disease. This review will focus specifically on the relevance of the mTOR pathway to gastric cancer pathogenesis and its potential as a therapeutic target in patients with gastric cancer.

The mTOR pathway

  1. Top of page
  2. Abstract
  3. The mTOR pathway
  4. Discussion
  5. Acknowledgements
  6. References

mTOR is a central regulatory kinase that increases the production of proteins that stimulate key cellular processes such as cell growth and proliferation, cell metabolism, and angiogenesis.16–18 mTOR increases translation of proteins that drive cell growth and cell division, such as cyclin D1, and decreases translation of negative regulators of cell cycle progression.19 mTOR plays a role in cellular metabolism by stimulating the surface expression of nutrient transporters,20 resulting in increased availability of nutrients to fulfill the energy and metabolic requirements for mTOR-activated cell growth and proliferation. mTOR also increases the translation of hypoxia-inducible factor-1α (HIF-1α), which drives the expression of angiogenic growth factors such as vascular endothelial growth factor (VEGF), resulting in new vasculature.18

mTOR integrates intracellular cues regarding nutrient and energy availability and signals from the growth factor pathways to directly mediate cellular processes via protein translation.21 Signaling to mTOR from growth factors has been well characterized and is mediated via the PI3K pathway through Akt and the tuberous sclerosis complex proteins TSC1 and TSC2, which form a dimer to regulate mTOR activity (Fig. 1). In physiologically normal cells, PI3K/Akt-mediated inactivation of TSC2 results in proteosomal degradation of the TSC1/TSC2 protein complex, thereby permitting mTOR activation.22, 23 Depending on available protein binding partners, mTOR can form one of two complexes: mTOR complex 1 (mTORC1), composed of mTOR plus FK506-binding protein 12 kDa (FKBP12), mammalian LST8 (mLST8), and the regulatory-associated protein of mTOR (raptor); or mTORC2, composed of mTOR plus the rapamycin-insensitive companion of mTOR (rictor), Sin1 and mLST8.24, 25 Activated mTORC1 phosphorylates two effector molecules, S6 kinase 1 (S6K1) and 4E-binding protein 1 (4E-BP1), to stimulate protein synthesis supporting cell growth and proliferation, cell metabolism and angiogenesis.16–18 Activated mTORC2 phosphorylates Akt leading to its full activation. The functions of mTORC2, which include regulating the actin cytoskeleton and cell survival, and its role in tumorigenesis are not yet well defined.24, 25 Pharmacologically, mTORC1 is sensitive to mTOR inhibition by rapamycin and rapamycin derivatives such as everolimus, an oral rapamycin derivative with improved pharmacokinetic properties.24, 26 mTORC2 is insensitive to rapamycin,24 although prolonged rapamycin treatment can result in mTORC2 inhibition potentially through irreversible mTOR sequestration, thus preventing mTORC2 formation.27 In addition, mTORC1-mediated S6K1 activation may inhibit mTORC2 via a negative feedback loop, resulting in suppressed Akt signaling.28, 29 This feedback loop was recently demonstrated in a preclinical study of gastrointestinal cancer cells.30 Akt activity is also attenuated by mTORC1-mediated S6K1 phosphorylation and subsequent proteolysis of insulin receptor substrate, which results in reduced PI3K/Akt signaling.28, 29

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Figure 1. The mTOR signaling pathway.

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Mutations in upstream components of the mTOR signaling pathway result in inappropriate mTOR activation,15 thus promoting tumor progression. In a genetic analysis of patients with esophageal cancer, mutations in Akt were associated with an increased risk of recurrence after chemotherapy, and mutations in phosphatase and tensin homolog (PTEN), a negative regulator of PI3K/Akt, was associated with a decreased risk of recurrence, possibly due to increased PTEN expression.31 Mutations in PI3K also have been noted.32 Regardless of the mechanism of aberrant mTOR activation, preclinical studies suggest that tumors with mutations in the mTOR pathway are uniquely susceptible to mTOR inhibitor therapy.33, 34 However, not all tumors with mTOR activation respond to mTOR inhibitor therapy. Possible explanations for this include the presence of a negative feedback loop resulting in increased PI3K/Akt/mTOR signaling even in the presence of rapamycin, involvement of mTORC2, and incomplete mTOR inhibition.35 Moreover, there are several mechanisms of drug resistance downstream of mTOR, including downregulation of 4E-BP1 and S6K1 mutations resulting in constitutive activation.36 Markers of drug-target inhibition have been developed, including inhibition of S6K1 activity in peripheral blood mononuclear cells (PBMCs), which correlated well with mTOR inhibitor exposure in clinical studies and preclinical models of human cancer.26 Further studies are needed to determine whether such pharmacodynamic measurements are useful in predicting outcomes. Clinical studies to determine relevant prognostic biomarkers to predict patient response to mTOR inhibitor therapy are ongoing.34

Preclinical rationale for mTOR inhibition in gastric cancer

Several preclinical studies have indicated dysregulation of mTOR activity in gastric cancer cell models, suggesting mTOR as a potential therapeutic target. Mutations in upstream regulators of mTOR signaling pathway epithelial growth factor receptor (EGFR),37 PI3K37, 38 and PTEN39 have been observed in patient-derived gastric tumor samples. In addition, preclinical studies have demonstrated evidence of mTOR activation in gastric cancer cells and tumors. Patient-derived gastric cancer samples have been shown to express phosphorylated mTOR indicative of mTOR activation,40–43 which has been positively correlated with tumor progression and poor survival in patients with gastric cancer.41, 43, 44

Treatment of gastric cancer cell lines with the mTOR inhibitors sirolimus or everolimus resulted in a decrease in phosphorylation of S6K1 and 4E-BP1 as well as attenuation of HIF-1α and VEGF.40, 45–47 Everolimus treatment also resulted in G1 cell cycle arrest and inhibited the proliferation of gastric cancer cell lines.45, 46, 48 Moreover, everolimus in combination with 5-FU, cisplatin, oxaliplatin or docetaxel resulted in synergistic growth inhibition of 5-FU-resistant gastric cancer cell lines.48 Consistent with the antiproliferative effects observed in vitro, mTOR inhibitors alone or in combination with other agents significantly delayed tumor progression in xenograft models of gastric cancer.40, 45

Everolimus in patients with gastric cancer

Currently, everolimus is the only mTOR inhibitor that has been investigated in phase I/II clinical trials of patients with advanced gastric cancer. In a phase I study of everolimus in 9 Japanese patients with advanced solid tumors, everolimus 10 mg day−1 resulted in a partial response with a duration of >4 months in a heavily pretreated patient with gastric cancer and liver metastases.49 Similarly, a phase I dose-escalation trial of everolimus (5–10 mg day−1) plus mitomycin C in 15 patients with advanced gastric cancer previously treated with platinum-based chemotherapy conducted in Europe also demonstrated antitumor activity. Of 13 evaluable patients, 3 (23%) experienced a partial response, one of which lasted for 1 year, and three patients had stable disease.50 There were no dose-limiting toxicities reported. Frequent grade 1/2 toxicities related to treatment included mucositis (61%), thrombocytopenia (54%), nausea (54%), leukopenia (46%), fatigue (31%) and diarrhea (23%). Grade 3/4 toxicities included leukopenia (15%), mucositis (8%), neutropenia (8%), lymphopenia (8%) and increased bilirubin (8%).50

In a recent phase II trial conducted in Japan, everolimus 10 mg day−1 was administered to 53 patients with metastatic gastric cancer previously treated with one (n = 27) or two (n = 26) prior chemotherapy regimens.51 The primary study end point was disease control rate, which was defined as the percentage of patients with a complete response, partial response, or stable disease as best overall response.51 The study showed an overall disease control rate of 56% (all with stable disease), and subgroup analyses indicated that the disease control rate benefit was consistent in patients receiving everolimus as a second- or third-line therapy.51 Although no complete or partial responses were documented, 45% of patients had a decrease in tumor size from baseline by independent radiologic review.51 Median progression-free survival was 2.7 months,51 suggesting that the primary benefit of everolimus was disease stabilization. Median overall survival was 10.1 months,51 although it may have been confounded by the 85% of patients who received additional chemotherapy after discontinuation from everolimus.51 Exploratory overall and progression-free survival subgroup analyses demonstrated that the survival benefit was consistent regardless of the number of chemotherapy regimens previously received.51 Everolimus therapy was generally well tolerated, and adverse events typically were grade 1 or 2 in severity.51 The most common adverse events were stomatitis (74%), anorexia (53%), fatigue (51%), rash (45%), nausea (32%), peripheral edema (23%), diarrhea (21%) and pruritus (19%).51 Grade 3 adverse events occurred in 20 patients and included anemia (9%), hyponatremia (9%), increased gamma-glutamyltransferase (8%) and lymphopenia (8%).51 Grade 4 adverse events that were considered to be possibly related to everolimus treatment occurred in four patients (tumor hemorrhage, increased γ-glutamyltransferase, lymphopenia, and cerebral infarction).51

The efficacy of everolimus in patients with previously treated metastatic gastric cancer was supported by preliminary results from a phase II study conducted in Korea. Of 54 patients with chemotherapy-refractory advanced gastric cancer treated with everolimus 10 mg day−1, 2 (4%) achieved confirmed partial responses and 19 (35%) had stable disease, resulting in a disease control rate of 39%. The 4-month progression-free survival rate, the primary end point, was 18.4% with a median progression-free survival of 1.7 months. Median overall survival was 8.3 months. Treatment was generally well tolerated; the most common grade 3/4 adverse events included hepatic dysfunction (11%), anemia (9%) and thrombocytopenia (9%).52

Discussion

  1. Top of page
  2. Abstract
  3. The mTOR pathway
  4. Discussion
  5. Acknowledgements
  6. References

Emerging treatment paradigms look promising for treating patients with advanced gastric cancer. However, additional work is needed to optimize treatment regimens and determine biomarkers predictive of therapeutic success. Available clinical trial data show that objective responses are rare in patients with gastric cancer receiving mTOR inhibitors. This raises questions regarding the prevalence of inappropriate mTOR activation in gastric cancer and whether the administration of mTOR inhibitors to unselected patient populations will be able to show expected results.

Patient selection based on molecular events known to be associated with mTOR activation such as the overexpression of PI3K/Akt and the growth factor receptors HER2 and insulin-like growth factor receptor (IGFR) as well as mutations in PI3K and mutations/amplifications of Akt or down regulation of PTEN may represent an appropriate way to identify populations that are more likely to show significant benefit from mTOR inhibitors. Unfortunately, little is known about the molecular profiles of patient who responded to everolimus in initial trials, although some clinical studies currently enrolling patients (NCT01049620, NCT00632268; Table 1) include biomarker analyses.

Table 1. Ongoing trials of everolimus in gastric cancer
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Two phase III trials evaluating everolimus in gastric cancer are ongoing. The GRANITE-1 (Gastric antitumor trial with everolimus-1) compares everolimus/supportive care with placebo/best supportive care in patients with advanced gastric cancer after progression on one or two prior systemic chemotherapies, with a target enrollment of 633 patients (NCT00879333). The primary end point is overall survival. The AIO-STO-0111 (RADPAC) trial, on the other hand, evaluates paclitaxel monotherapy with or without everolimus in the second- or third-line setting. The study is conducted by the German Arbeitsgemeinschaft Internistische Onkologie, with a target enrollment of 480 patients and overall survival as the primary end point (NCT01248403). Both of these phase III studies involve administration of everolimus to unselected patient populations, and both are accompanied by exploratory biomarker research programs that will examine the predictive relationship of phosphorylated S6K1, HER2, phosphorylated Akt, HIF-2α, PTEN, cyclin D1, Ki-67 frequency, p53 and CC3, as well as the mutational status of PI3K catalytic subunit and PTEN, with efficacy endpoints. Irrespective of whether the studies will meet their primary end points, it will be very important to identify potential markers of response to everolimus and validate their role in future studies. However, the appropriate assessment of biomarkers remains challenging. The quantification of immunohistochemistry with cyclin D1, PTEN and phospho-specific antibodies in formalin-fixed tissues of solid tumors has not been fully standardized, and significant concerns exist about the stability of phospho-proteins, which are known to be influenced by type of sampling (e.g., biopsy versus surgical resection) and subsequent processing.

Another path to improve efficacy of mTOR inhibitors is combination with either cytotoxic agents or other targeted therapies. Based on preclinical studies showing synergistic effects with some cytotoxic agents,34 some ongoing clinical studies currently are evaluating everolimus in patients with gastric cancer in combination with chemotherapeutic agents (Table 1). The finding that mTOR inhibition has been shown to induce feedback activation of Akt provides a rationale for the combination of mTOR inhibitors with targeted drugs that can inhibit Akt activation such as small-molecule inhibitors of Akt, the anti-HER2 antibody trastuzumab and IGF-IR inhibitors. A recent phase III trial demonstrated that the addition of trastuzumab to chemotherapy improved outcomes in patients with metastatic gastric cancer who overexpressed HER2,53 a feature found in ∼20% of patients.54 Notably, loss of PTEN, a negative regulator of PI3K/Akt/mTOR, has been shown to mediate trastuzumab resistance.55, 56 Taken together, the data provide a foundation to evaluate the combination of mTOR inhibitors and trastuzumab in HER2-positive gastric cancer.

To more effectively inhibit the mTOR pathway, it will also be important to better understand the role of mTOR-dependent networks, its relationship to compensatory pathways, and the contribution of mTORC2 in the progression of gastric cancer. This increased knowledge can provide the foundation for generating novel strategies to improve therapeutic success. For example, it has been hypothesized that inhibition of both mTORC1 and mTORC2 would be a more effective way of treating tumors, as the presence of feedback loops (e.g., via Akt and RAS/MAPK signaling) and the possible contribution of mTORC2 to tumor progression may reduce the efficacy of mTORC1 inhibitors.27–29 To circumvent these potential limitations, novel inhibitors of both mTORC1 and mTORC2 (e.g., OSI-027, BEZ235 and XL765) are being currently evaluated in phase I/II trials of patients with solid tumors.57

Acknowledgements

  1. Top of page
  2. Abstract
  3. The mTOR pathway
  4. Discussion
  5. Acknowledgements
  6. References

The authors thank Scientific Connexions, Newtown, PA, USA for providing assistance with medical writing and editing. S.E. Al-Batran has received research funding from and serves in an advisory role for Novartis Pharmaceuticals Corporation. M. Ducreux has received research funding (French investigator for the GRANITE study) from and served as a speaker for Novartis Pharmaceuticals Corporation. A. Ohtsu declares no conflicts of interest.

References

  1. Top of page
  2. Abstract
  3. The mTOR pathway
  4. Discussion
  5. Acknowledgements
  6. References
  • 1
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008, cancer incidence and mortality worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer, 2010. Available at: http://globocan.iarc.fr.
  • 2
    Menges M, Hoehler T. Current strategies in systemic treatment of gastric cancer and cancer of the gastroesophageal junction. J Cancer Res Clin Oncol 2009; 135: 2938.
  • 3
    Ajani JA. Evolving chemotherapy for advanced gastric cancer. Oncologist 2005; 10: 4958.
  • 4
    Webb A, Cunningham D, Scarffe JH, Harper P, Norman A, Joffe JK, Hughes M, Mansi J, Findlay M, Hill A, Oates J, Nicolson M, et al. Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 1997; 15: 2617.
  • 5
    Ross P, Nicolson M, Cunningham D, Valle J, Seymour M, Harper P, Price T, Anderson H, Iveson T, Hickish T, Lofts F, Norman A. Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) with epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol 2002; 20: 19962004.
  • 6
    Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J, Lichinitser M, Guan Z, Khasanov R, Zheng L, Philco-Salas M, Suarez T, et al. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as firstline therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol 2009; 20: 66673.
  • 7
    Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Risse ML, Ajani JA, et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil and first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol 2006; 24: 49917.
  • 8
    Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; 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: 3646.
  • 9
    Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, Rethwisch V, Seipelt G, Homann N, Wilhelm G, Schuch G, Stoehlmacher J, et al. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol 2008; 26: 143542.
  • 10
    Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, Miyashita K, Nishizaki T, Kobayashi O, Takiyama W, Toh Y, Nagaie 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: 21521.
  • 11
    Yoshikawa T, Tsuburaya A, Shimada K, Sato A, Takahashi M, Koizumi W, Yoshizawa Y, Nabeshima K, Kimura M, Hataya K, Kobayashi O. A phase II study of doxifluridine and docetaxel combination chemotherapy for advanced or recurrent gastric cancer. Gastric Cancer 2009; 12: 2128.
  • 12
    Kakeji Y, Oki E, Egashira A, Sadanaga N, Takahashi I, Morita M, Emi Y, Maehara Y. Phase II study of biweekly docetaxel and S-1 combination therapy for advanced or recurrent gastric cancer. Oncology 2009; 77: 4952.
  • 13
    Koizumi W, Takiuchi H, Yamada Y, Boku N, Fuse N, Muro K, Komatsu Y, Tsuburaya A. Phase II study of oxaliplatin plus S-1 as first-line treatment for advanced gastric cancer (G-SOX study). Ann Oncol 2010; 21: 10015.
  • 14
    Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol 2008; 19: 15239.
  • 15
    Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer 2004; 4: 33548.
  • 16
    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: 20016.
  • 17
    Edinger AL, Thompson CB. Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake. Mol Biol Cell 2002; 13: 227688.
  • 18
    Patel PH, Chadalavada RS, Chaganti RS, Motzer RJ. Targeting von Hippel-Lindau pathway in renal cell carcinoma. Clin Cancer Res 2006; 12: 721520.
  • 19
    Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2004; 18: 192645.
  • 20
    Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006; 124: 47184.
  • 21
    Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and aging. Nat Rev Mol Cell Biol 2011; 12: 2135.
  • 22
    Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002; 4: 64857.
  • 23
    Dan HC, Sun M, Yang L, Feldman RI, Sui XM, Ou CC, Nellist M, Yeung RS, Halley DJ, Nicosia SV, Pledger WJ, Cheng JQ. Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin. J Biol Chem 2002; 277: 3536470.
  • 24
    Yang Q, Guan KL. Expanding mTOR signaling. Cell Res 2007; 17: 66681.
  • 25
    Sarbassov DD, Ali SM, Sabatini DM. Growing roles for the mTOR pathway. Curr Opin Cell Biol 2005; 17: 596603.
  • 26
    O'Reilly T, McSheehy PM. Biomarker development for the clinical activity of the mTOR inhibitor everolimus (RAD001): processes, limitations, and further proposals. Transl Oncol 2010; 3: 6579.
  • 27
    Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 2006; 22: 15968.
  • 28
    Wander SA, Hennessy BT, Slingerland JM. Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy. J Clin Invest 2011; 121: 123141.
  • 29
    Dowling RJ, Topisirovic I, Fonseca BD, Sonenberg N. Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochim Biophys Acta 2010; 1804: 4339.
  • 30
    Lang SA, Hackl C, Moser C, Fichtner-Feigl S, Koehl GE, Schlitt HJ, Geissler EK, Stoeltzing O. 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: 43542.
  • 31
    Hildebrandt MA, Yang H, Hung MC, Izzo JG, Huang M, Lin J, Ajani JA, Wu X. Genetic variations in the PI3K/PTEN/AKT/mTOR pathway are associated with clinical outcomes in esophageal cancer patients treated with chemoradiotherapy. J Clin Oncol 2009; 27: 85771.
  • 32
    Velho S, Oliveira C, Ferreira A, Ferreira AC, Suriano G, Schwartz S, Jr, Duval A, Carneiro F, Machado JC, Hamelin R, Seruca R. The prevalence of PIK3CA mutations in gastric and colon cancer. Eur J Cancer 2005; 41: 164954.
  • 33
    Di Nicolantonio F, Arena S, Tabernero J, Grosso S, Molinari F, Macarulla T, Russo M, Cancelliere C, Zecchin D, Mazzucchelli L, Sasazuki T, Shirasawa S, et al. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest 2010; 120: 285866.
  • 34
    Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol 2009; 27: 227887.
  • 35
    Liu Q, Thoreen C, Wang J, Sabatini D, Gray NS. mTOR mediated anti-cancer drug discovery. Drug Discov Today Ther Strateg 2009; 6: 4755.
  • 36
    Huang S, Bjornsti MA, Houghton PJ. Rapamycins: mechanism of action and cellular resistance. Cancer Biol Ther 2003; 2: 22232.
  • 37
    Corso G, Velho S, Paredes J, Pedrazzani C, Martins D, Milanezi F, Pascale V, Vindigni C, Pinheiro H, Leite M, Marrelli D, Sousa S, et al. Oncogenic mutations in gastric cancer with microsatellite instability. Eur J Cancer 2011; 47: 44351.
  • 38
    Li VS, Wong CW, Chan TL, Chan AS, Zhao W, Chu KM, So S, Chen X, Yuen ST, Leung SY. Mutations of PIK3CA in gastric adenocarcinoma. BMC Cancer 2005; 5: 29.
  • 39
    Wen YG, Wang Q, Zhou CZ, Qiu GQ, Peng ZH, Tang HM. Mutation analysis of tumor suppressor gene PTEN in patients with gastric carcinomas and its impact on PI3K/AKT pathway. Oncol Rep 2010; 24: 8995.
  • 40
    Lang SA, Gaumann A, Koehl GE, Seidel U, Bataille F, Klein D, Ellis LM, Bolder U, Hofstaedter F, Schlitt HJ, Geissler EK, Stoeltzing O. 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: 180310.
  • 41
    Murayama T, Inokuchi M, Takagi Y, Yamada H, Kojima K, Kumagai J, Kawano T, Sugihara K. Relation between outcomes and localisation of p-mTOR expression in gastric cancer. Br J Cancer 2009; 100: 7828.
  • 42
    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.
  • 43
    Yu G, Wang J, Chen Y, Wang X, Pan J, Li G, Jia Z, Li Q, Yao JC, Xie K. Overexpression of phosphorylated mammalian target of rapamycin predicts lymph node metastasis and prognosis of chinese patients with gastric cancer. Clin Cancer Res 2009; 15: 18219.
  • 44
    An JY, Kim KM, Choi MG, Noh JH, Sohn TS, Bae JM, Kim S. Prognostic role of p-mTOR expression in cancer tissues and metastatic lymph nodes in pT2b gastric cancer. Int J Cancer 2010; 126: 290413.
  • 45
    Cejka D, Preusser M, Woehrer A, Sieghart W, Strommer S, Werzowa J, Fuereder T, Wacheck V. Everolimus (RAD001) and anti-angiogenic cyclophosphamide show long-term control of gastric cancer growth in vivo. Cancer Biol Ther 2008; 7: 137785.
  • 46
    Fuereder T, Jaeger-Lansky A, Hoeflmayer D, Preusser M, Strommer S, Cejka D, Koehrer S, Crevenna R, Wacheck V. mTOR inhibition by everolimus counteracts VEGF induction by sunitinib and improves anti-tumor activity against gastric cancer in vivo. Cancer Lett 2010; 296: 24956.
  • 47
    Shigematsu H, Yoshida K, Sanada Y, Osada S, Takahashi T, Wada Y, Konishi K, Okada M, Fukushima M. Rapamycin enhances chemotherapy-induced cytotoxicity by inhibiting the expressions of TS and ERK in gastric cancer cells. Int J Cancer 2010; 126: 271625.
  • 48
    Lee KH, Hur HS, Im SA, Lee J, Kim HP, Yoon YK, Han SW, Song SH, Oh DY, Kim TY, Bang YJ. RAD001 shows activity against gastric cancer cells and overcomes 5-FU resistance by downregulating thymidylate synthase. Cancer Lett 2010; 299: 228.
  • 49
    Okamoto I, Doi T, Ohtsu A, Miyazaki M, Tsuya A, Kurei K, Kobayashi K, Nakagawa K. Phase I clinical and pharmacokinetic study of RAD001 (everolimus) administered daily to Japanese patients with advanced solid tumors. Jpn J Clin Oncol 2010; 40: 1723.
  • 50
    Pauligk C, Janowski S, Steinmetz K, Atmaca A, Pustowka A, Jaeger E, Al-Batran S. Daily RAD001 plus mitomycin C, every three weeks in previously treated patients with advanced gastric cancer or cancer of the esophagogastric junction: preliminary results of a phase I study. J Clin Oncol 2010; 28( suppl): abstract e14531. Available at: http://www.asco.org/ASCOv2/Meetings/Abstracts?& vmview=abst_detail_view&confID=74& abstractID=43251.
  • 51
    Doi T, Muro K, Boku N, Yamada Y, Nishina T, Takiuchi H, Komatsu Y, Hamamoto Y, Ohno N, Fujita Y, Robson M, Ohtsu A. Multicenter phase II study of everolimus in patients with previously treated metastatic gastric cancer. J Clin Oncol 2010; 28: 190410.
  • 52
    Yoon DH, Ryu MH, Lee JL, Ryoo B, Chang H, Kim TW, Lee C, Park YS, Kang Y. Phase II study of everolimus in patients with advanced gastric cancer refractory to chemotherapy including fluoropyrimidine and platinum. Ann Oncol 2010; 21( suppl 8):abstract P725.
  • 53
    Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, et al. 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: 68797.
  • 54
    Kim MA, Jung EJ, Lee HS, Lee HE, Jeon YK, Yang HK, Kim WH. Evaluation of HER-2 gene status in gastric carcinoma using immunohistochemistry, fluorescence in situ hybridization, and real-time quantitative polymerase chain reaction. Hum Pathol 2007; 38: 138693.
  • 55
    Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, Hortobagyi GN, Hung MC, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004; 6: 11727.
  • 56
    Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M, Beijersbergen RL, Mills GB, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 2007; 12: 395402.
  • 57
    Furic L, Livingstone M, Dowling RJ, Sonenberg N. Targeting mTOR-dependent tumours with specific inhibitors: a model for personalized medicine based on molecular diagnoses. Curr Oncol 2009; 16: 5961.