mTOR pathway in colorectal cancer: an update

The mammalian target of rapamycin (mTOR) has emerged as a potential target for drug development, particularly due to the fact that it plays such a crucial role in cancer biology. In addition, next-generation mTOR inhibitors have become available, marking an exciting new phase in mTOR-based therapy. However, the verdict on their therapeutic efectiveness remains unclear. Here we review phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR signaling as one of the primary mechanisms for sustaining tumor outgrowth and metastasis, recent advances in the development of mTOR inhibitors, and current studies addressing mTOR activation/inhibition in colorectal cancer (CRC). We will also discuss our recent comparative study of diferent mTOR inhibitors in a population of colon cancer stem cells (CSCs), and current major challenges for achieving individualized drug therapy using kinase inhibitors.

[1]  Wei Wang,et al.  Transient PI3K Inhibition Induces Apoptosis and Overcomes HGF-Mediated Resistance to EGFR-TKIs in EGFR Mutant Lung Cancer , 2011, Clinical Cancer Research.

[2]  A. Maitra,et al.  Superior efficacy of co-treatment with dual PI3K/mTOR inhibitor NVP-BEZ235 and pan-histone deacetylase inhibitor against human pancreatic cancer , 2012, Oncotarget.

[3]  Daniela Gabriel,et al.  Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity , 2008, Molecular Cancer Therapeutics.

[4]  James S. Duncan,et al.  Combined PI3K/mTOR and MEK Inhibition Provides Broad Antitumor Activity in Faithful Murine Cancer Models , 2012, Clinical Cancer Research.

[5]  Hang Zheng,et al.  Targeting of mTORC2 prevents cell migration and promotes apoptosis in breast cancer , 2012, Breast Cancer Research and Treatment.

[6]  M. Blagosklonny.  Cell cycle arrest is not yet senescence, which is not just cell cycle arrest: terminology for TOR-driven aging , 2012, Aging.

[7]  Philippe P Roux,et al.  mTORC1-Activated S6K1 Phosphorylates Rictor on Threonine 1135 and Regulates mTORC2 Signaling , 2009, Molecular and Cellular Biology.

[8]  K. Pienta,et al.  Copy number and targeted mutational analysis reveals novel somatic events in metastatic prostate tumors. , 2011, Genome research.

[9]  H. Aburatani,et al.  Genotype-dependent efficacy of a dual PI3K/mTOR inhibitor, NVP-BEZ235, and an mTOR inhibitor, RAD001, in endometrial carcinomas. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  P. Nowell.  The clonal evolution of tumor cell populations. , 1976, Science.

[11]  J. Blenis,et al.  Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. , 2002, Genes & development.

[12]  A. Jemal,et al.  Cancer Statistics, 2010 , 2010, CA: a cancer journal for clinicians.

[13]  K. Tachibana,et al.  Dual blocking of mTor and PI3K elicits a prodifferentiation effect on glioblastoma stem-like cells. , 2010, Neuro-oncology.

[14]  M. Antoch,et al.  Rapamycin extends lifespan and delays tumorigenesis in heterozygous p53+/− mice , 2012, Aging.

[15]  F. Khuri,et al.  The Combination of RAD001 and NVP-BEZ235 Exerts Synergistic Anticancer Activity against Non-Small Cell Lung Cancer In Vitro and In Vivo , 2011, PloS one.

[16]  J. Heitman,et al.  Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast , 1991, Science.

[17]  J. Heitman,et al.  TOR Mutations Confer Rapamycin Resistance by Preventing Interaction with FKBP12-Rapamycin (*) , 1995, The Journal of Biological Chemistry.

[18]  Antitumor activities of ATP-competitive inhibitors of mTOR in colon cancer cells , 2012, BMC Cancer.

[19]  C. Chresta,et al.  Abstract 917: AZD2014, a dual mTORC1 and mTORC2 inhibitor is differentiated from allosteric inhibitors of mTORC1 in ER+ breast cancer , 2012 .

[20]  T. Chou,et al.  Utility of a PI3K/mTOR Inhibitor (NVP-BEZ235) for Thyroid Cancer Therapy , 2012, PloS one.

[21]  C. Chresta,et al.  Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR) , 2009, The Biochemical journal.

[22]  B. Park,et al.  PIK3CA and KRAS mutations predict for response to everolimus therapy: now that's RAD001. , 2010, The Journal of clinical investigation.

[23]  C. Eng,et al.  Hamartomatous polyposis syndromes , 2007, Nature Clinical Practice Gastroenterology &Hepatology.

[24]  Lin Wang,et al.  Targeting TORC1/2 enhances sensitivity to EGFR inhibitors in head and neck cancer preclinical models. , 2012, Neoplasia.

[25]  Gurpreet W. Tang,et al.  Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes , 2009, Nature.

[26]  A. Tischler,et al.  Combined inhibition of mTORC1 and mTORC2 signaling pathways is a promising therapeutic option in inhibiting pheochromocytoma tumor growth: in vitro and in vivo studies in female athymic nude mice. , 2013, Endocrinology.

[27]  J. Baselga,et al.  Dual Mtorc1/2 and Her2 Blockade Results in Antitumor Activity in Preclinical Models of Breast Cancer Resistant to Anti-her2 Therapy Statement of Translational Relevance , 2022 .

[28]  Ted Powers,et al.  Caffeine Targets TOR Complex I and Provides Evidence for a Regulatory Link between the FRB and Kinase Domains of Tor1p* , 2006, Journal of Biological Chemistry.

[29]  H. Weiss,et al.  mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. , 2011, Cancer research.

[30]  D. Sabatini,et al.  mTOR Mediated Anti-Cancer Drug Discovery. , 2009, Drug discovery today. Therapeutic strategies.

[31]  P. L. Yen,et al.  The efficacy of a novel, dual PI3K/mTOR inhibitor NVP‐BEZ235 to enhance chemotherapy and antiangiogenic response in pancreatic cancer , 2012, Journal of cellular biochemistry.

[32]  J. Lehár,et al.  RAD001 Enhances the Potency of BEZ235 to Inhibit mTOR Signaling and Tumor Growth , 2012, PloS one.

[33]  J. Gera,et al.  Mammalian Target of Rapamycin Inhibitors Induce Tumor Cell Apoptosis In Vivo Primarily by Inhibiting VEGF Expression and Angiogenesis , 2013, Journal of oncology.

[34]  D. Hedley,et al.  Activity of a novel, dual PI3-kinase/mTor inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthotopic xenografts , 2009, British Journal of Cancer.

[35]  Mitchel S. Berger,et al.  Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide. , 2011, Neuro-oncology.

[36]  H. Lane,et al.  Equivalent benefit of mTORC1 blockade and combined PI3K-mTOR blockade in a mouse model of tuberous sclerosis , 2009, Molecular Cancer.

[37]  Kwok-Kin Wong,et al.  Differential induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition , 2009, Proceedings of the National Academy of Sciences.

[38]  Ninib Baryawno,et al.  Effects of small molecule inhibitors of PI3K/Akt/mTOR signaling on neuroblastoma growth in vitro and in vivo , 2011, International journal of cancer.

[39]  M. Antoch,et al.  New nanoformulation of rapamycin Rapatar extends lifespan in homozygous p53−/− mice by delaying carcinogenesis , 2012, Aging.

[40]  Won-Suk Jang,et al.  Coexistent mutations of KRAS and PIK3CA affect the efficacy of NVP‐BEZ235, a dual PI3K/MTOR inhibitor, in regulating the PI3K/MTOR pathway in colorectal cancer , 2013, International journal of cancer.

[41]  Guoqiang Chen,et al.  mTOR Signaling Pathway Is a Target for the Treatment of Colorectal Cancer , 2009, Annals of Surgical Oncology.

[42]  N. Munshi,et al.  Antimyeloma activity of the orally bioavailable dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235. , 2009, Cancer research.

[43]  B. Xing,et al.  Inhibition of PI3K/AKT/mTOR pathway enhances temozolomide-induced cytotoxicity in pituitary adenoma cell lines in vitro and xenografted pituitary adenoma in female nude mice. , 2013, Endocrinology.

[44]  R. Iglesias-Bartolome,et al.  Signaling circuitries controlling stem cell fate: to be or not to be. , 2011, Current opinion in cell biology.

[45]  S. Wiemann,et al.  Combinatorial targeting of FGF and ErbB receptors blocks growth and metastatic spread of breast cancer models , 2013, Breast Cancer Research.

[46]  S. Grant,et al.  Dual inhibition of Bcl-2 and Bcl-xL strikingly enhances PI3K inhibition-induced apoptosis in human myeloid leukemia cells through a GSK3- and Bim-dependent mechanism. , 2013, Cancer Research.

[47]  Christine C. Hudson,et al.  A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. , 2000, Cancer research.

[48]  A. Gudkov,et al.  Hypoxia suppresses conversion from proliferative arrest to cellular senescence , 2012, Proceedings of the National Academy of Sciences.

[49]  J. Asara,et al.  Stimulation of de Novo Pyrimidine Synthesis by Growth Signaling Through mTOR and S6K1 , 2013, Science.

[50]  P. N. Rao,et al.  Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification , 2001, Science.

[51]  J. Baselga,et al.  NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. , 2008, Cancer research.

[52]  L. Chodosh,et al.  mTOR mediates Wnt-induced epidermal stem cell exhaustion and aging. , 2009, Cell stem cell.

[53]  N. Pavletich,et al.  mTOR kinase structure, mechanism and regulation by the rapamycin-binding domain , 2013, Nature.

[54]  M. Waterfield,et al.  Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases. , 2007, Cancer research.

[55]  C. Antonescu,et al.  Acquired Resistance to Imatinib in Gastrointestinal Stromal Tumor Occurs Through Secondary Gene Mutation , 2005, Clinical Cancer Research.

[56]  Q. Xue,et al.  Palomid 529, a novel small-molecule drug, is a TORC1/TORC2 inhibitor that reduces tumor growth, tumor angiogenesis, and vascular permeability. , 2008, Cancer research.

[57]  D. Leroith,et al.  Inhibiting PI3K reduces mammary tumor growth and induces hyperglycemia in a mouse model of insulin resistance and hyperinsulinemia , 2011, Oncogene.

[58]  Lorenzo Galluzzi,et al.  TP53 and MTOR crosstalk to regulate cellular senescence , 2010, Aging.

[59]  T. Maeda,et al.  Isolation of Hyperactive Mutants of Mammalian Target of Rapamycin* , 2008, Journal of Biological Chemistry.

[60]  D. Guertin,et al.  Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR Complex , 2005, Science.

[61]  V. Zinzalla,et al.  Activation of mTORC2 by Association with the Ribosome , 2011, Cell.

[62]  E. Kikuchi,et al.  Dual PI3K/mTOR inhibitor NVP-BEZ235 sensitizes docetaxel in castration resistant prostate cancer. , 2014, The Journal of urology.

[63]  G. Koehl,et al.  Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor , 2002, Nature Medicine.

[64]  C. James,et al.  Akt and Autophagy Cooperate to Promote Survival of Drug-Resistant Glioma , 2010, Science Signaling.

[65]  D. Stolz,et al.  A stochastic model for cancer stem cell origin in metastatic colon cancer. , 2008, Cancer research.

[66]  Suimin Qiu,et al.  Targeted Inhibition of Mammalian Target of Rapamycin Signaling Inhibits Tumorigenesis of Colorectal Cancer , 2009, Clinical Cancer Research.

[67]  F. Khuri,et al.  Augmentation of NVP-BEZ235's anticancer activity against human lung cancer cells by blockage of autophagy , 2011, Cancer biology & therapy.

[68]  D. Sabatini,et al.  Mammalian Target of Rapamycin ( mTOR ) Inhibitor for Treatment of Cancer , 2011 .

[69]  S. Schreiber,et al.  Identification of an 11-kDa FKBP12-rapamycin-binding domain within the 289-kDa FKBP12-rapamycin-associated protein and characterization of a critical serine residue. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[70]  A. Nakashima,et al.  Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer , 2010, Oncogene.

[71]  C. Livi,et al.  Rapamycin extends life span of Rb1+/− mice by inhibiting neuroendocrine tumors , 2013, Aging.

[72]  N. Demartines,et al.  Targeting mTORC2 inhibits colon cancer cell proliferation in vitro and tumor formation in vivo , 2010, Molecular Cancer.

[73]  E. Giang,et al.  Corrigendum to “Radiosensitization of prostate cancer cells by the dual PI3K/mTOR inhibitor BEZ235 under normoxic and hypoxic conditions” [Radiother Oncol 106 (2013) 138–146]☆ , 2013 .

[74]  B. Evers,et al.  Roles of Phosphatidylinositol 3′-Kinase and Mammalian Target of Rapamycin/p70 Ribosomal Protein S6 Kinase in K-Ras-Mediated Transformation of Intestinal Epithelial Cells , 2004, Cancer Research.

[75]  T. Nakagawa,et al.  The novel phosphoinositide 3‐kinase–mammalian target of rapamycin inhibitor, BEZ235, circumvents erlotinib resistance of epidermal growth factor receptor mutant lung cancer cells triggered by hepatocyte growth factor , 2013, International journal of cancer.

[76]  Paul Workman,et al.  Molecular pharmacology of phosphatidylinositol 3-kinase inhibition in human glioma , 2009, Cell cycle.

[77]  P. Houghton,et al.  Preclinical Characterization of OSI-027, a Potent and Selective Inhibitor of mTORC1 and mTORC2: Distinct from Rapamycin , 2011, Molecular Cancer Therapeutics.

[78]  H. Zhang,et al.  Dual targeting of mTORC1/C2 complexes enhances histone deacetylase inhibitor-mediated anti-tumor efficacy in primary HCC cancer in vitro and in vivo. , 2012, Journal of hepatology.

[79]  Joshua M. Korn,et al.  Comprehensive genomic characterization defines human glioblastoma genes and core pathways , 2008, Nature.

[80]  N. Salesi,et al.  [Hamartomatous polyposis syndromes]. , 2004, Recenti progressi in medicina.

[81]  Dudley Lamming,et al.  mTORC1 in the Paneth cell niche couples intestinal stem cell function to calorie intake , 2012, Nature.

[82]  Zhaoshi Jiang,et al.  Phosphoproteomic Analysis Implicates the mTORC2-FoxO1 Axis in VEGF Signaling and Feedback Activation of Receptor Tyrosine Kinases , 2013, Science Signaling.

[83]  Qiang Yu,et al.  B55β-associated PP2A complex controls PDK1-directed myc signaling and modulates rapamycin sensitivity in colorectal cancer. , 2010, Cancer cell.

[84]  Alfredo Quiñones-Hinojosa,et al.  Oxygen in stem cell biology: a critical component of the stem cell niche. , 2010, Cell stem cell.

[85]  N. Sonenberg,et al.  eIF4E/4E-BP ratio predicts the efficacy of mTOR targeted therapies. , 2012, Cancer research.

[86]  C. Kuntner,et al.  Gastric Cancer Growth Control by BEZ235 In Vivo Does Not Correlate with PI3K/mTOR Target Inhibition but with [18F]FLT Uptake , 2011, Clinical Cancer Research.

[87]  C. Schnell,et al.  Effects of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 on the tumor vasculature: implications for clinical imaging. , 2008, Cancer research.

[88]  D. Alessi,et al.  Effect of PI3K- and mTOR-specific inhibitors on spontaneous B-cell follicular lymphomas in PTEN/LKB1-deficient mice , 2011, British Journal of Cancer.

[89]  Arata Tomiyama,et al.  Crosstalk Between the PI3K/mTOR and MEK/ERK Pathways Involved in the Maintenance of Self‐Renewal and Tumorigenicity of Glioblastoma Stem‐Like Cells , 2010, Stem cells.

[90]  E. Lagasse,et al.  Cancer Stem Cells: A Moving Target , 2013, Current Pathobiology Reports.

[91]  D. McDonald,et al.  Reduced VEGF production, angiogenesis, and vascular regrowth contribute to the antitumor properties of dual mTORC1/mTORC2 inhibitors. , 2011, Cancer research.

[92]  T. Golub,et al.  mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways , 2004, Nature Medicine.

[93]  K. Shokat,et al.  Autophagy suppression promotes apoptotic cell death in response to inhibition of the PI3K—mTOR pathway in pancreatic adenocarcinoma , 2011, Journal of Molecular Medicine.

[94]  K. Camphausen,et al.  Competitive but Not Allosteric mTOR Kinase Inhibition Enhances Tumor Cell Radiosensitivity. , 2013, Translational oncology.

[95]  J. Gera,et al.  Targeting TORC2 in multiple myeloma with a new mTOR kinase inhibitor. , 2010, Blood.

[96]  N. Demartines,et al.  The inhibition of MAPK potentiates the anti-angiogenic efficacy of mTOR inhibitors. , 2011, Biochemical and biophysical research communications.

[97]  J. Ptak,et al.  High Frequency of Mutations of the PIK3CA Gene in Human Cancers , 2004, Science.

[98]  Jianren Gu,et al.  Transient mTOR Inhibition Facilitates Continuous Growth of Liver Tumors by Modulating the Maintenance of CD133+ Cell Populations , 2011, PloS one.

[99]  L. Donehower.  Rapamycin as longevity enhancer and cancer preventative agent in the context of p53 deficiency , 2012, Aging.

[100]  Gordon B Mills,et al.  mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. , 2006, Cancer research.

[101]  C. Schnell,et al.  Targeting Melanoma with Dual Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Inhibitors , 2009, Molecular Cancer Research.

[102]  Erin M. Coffee,et al.  The Dual PI3K/mTOR Inhibitor NVP-BEZ235 Induces Tumor Regression in a Genetically Engineered Mouse Model of PIK3CA Wild-Type Colorectal Cancer , 2011, PloS one.

[103]  M. Lim,et al.  The dual PI3K/mTOR inhibitor, NVP-BEZ235, is efficacious against follicular lymphoma , 2010, Leukemia.

[104]  D. Alessi,et al.  mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). , 2008, The Biochemical journal.

[105]  Yiling Lu,et al.  AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. , 2009, Cancer cell.

[106]  L. Aaltonen,et al.  PTEN mutational spectra, expression levels, and subcellular localization in microsatellite stable and unstable colorectal cancers. , 2002, The American journal of pathology.

[107]  E. Lagasse,et al.  Selective targeting of human colon cancer stem-like cells by the mTOR inhibitor Torin-1 , 2013, Oncotarget.

[108]  N. Demartines,et al.  Targeting renal cell carcinoma with NVP-BEZ235, a dual PI3K/mTOR inhibitor, in combination with sorafenib , 2011, Molecular Cancer.

[109]  D. Sabatini,et al.  Discovery of 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one as a highly potent, selective mammalian target of rapamycin (mTOR) inhibitor for the treatment of cancer. , 2010, Journal of medicinal chemistry.

[110]  W. Yung,et al.  NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas , 2009, Molecular Cancer Therapeutics.

[111]  William A Weiss,et al.  A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. , 2006, Cancer cell.

[112]  K. M. Chen,et al.  Dual Targeting of Phosphoinositide 3-Kinase and Mammalian Target of Rapamycin Using NVP-BEZ235 as a Novel Therapeutic Approach in Human Ovarian Carcinoma , 2011, Clinical Cancer Research.

[113]  H. Lane,et al.  Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in ApcΔ716 mice , 2008, Proceedings of the National Academy of Sciences.

[114]  K. Shokat,et al.  Targeted polypharmacology: Discovery of dual inhibitors of tyrosine and phosphoinositide kinases , 2008, Nature chemical biology.

[115]  P. Pandolfi,et al.  Keloid disease can be inhibited by antagonizing excessive mTOR signaling with a novel dual TORC1/2 inhibitor. , 2012, The American journal of pathology.

[116]  James B. Mitchell,et al.  mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis. , 2012, Cell stem cell.

[117]  A. Gazdar,et al.  Dual phosphoinositide 3-kinase/mammalian target of rapamycin blockade is an effective radiosensitizing strategy for the treatment of non-small cell lung cancer harboring K-RAS mutations. , 2009, Cancer research.

[118]  P. Hammerman,et al.  The Pim kinases control rapamycin-resistant T cell survival and activation , 2005, The Journal of experimental medicine.

[119]  P. Schultz,et al.  Combination Therapy Targeting Both Tumor-Initiating and Differentiated Cell Populations in Prostate Carcinoma , 2010, Clinical Cancer Research.

[120]  M. Hall,et al.  Rapamycin passes the torch: a new generation of mTOR inhibitors , 2011, Nature Reviews Drug Discovery.

[121]  B. Evers,et al.  The role of PI3K/mTOR inhibition in combination with sorafenib in hepatocellular carcinoma treatment. , 2012, Anticancer research.

[122]  S. Fulda,et al.  PI3K inhibitors prime neuroblastoma cells for chemotherapy by shifting the balance towards pro-apoptotic Bcl-2 proteins and enhanced mitochondrial apoptosis , 2011, Oncogene.

[123]  Hans Clevers,et al.  Crypt stem cells as the cells-of-origin of intestinal cancer , 2009, Nature.

[124]  T. Hoppo,et al.  The mouse lymph node as an ectopic transplantation site for multiple tissues , 2012, Nature Biotechnology.

[125]  K. Shokat,et al.  Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells. , 2008, The Journal of clinical investigation.

[126]  Fenggui Wei,et al.  Combination of mTOR and EGFR Kinase Inhibitors Blocks mTORC1 and mTORC2 Kinase Activity and Suppresses the Progression of Colorectal Carcinoma , 2013, PloS one.

[127]  Khin Thway,et al.  Dual Blockade of the PI3K/AKT/mTOR (AZD8055) and RAS/MEK/ERK (AZD6244) Pathways Synergistically Inhibits Rhabdomyosarcoma Cell Growth In Vitro and In Vivo , 2013, Clinical Cancer Research.

[128]  J. Tamburini,et al.  The dual mTORC1 and mTORC2 inhibitor AZD8055 has anti-tumor activity in acute myeloid leukemia , 2012, Leukemia.

[129]  R. Abraham,et al.  Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2. , 2010, Cancer research.

[130]  R. Deng,et al.  Dual Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Inhibitor NVP-BEZ235 Has a Therapeutic Potential and Sensitizes Cisplatin in Nasopharyngeal Carcinoma , 2013, PloS one.

[131]  B. Nelkin,et al.  Synergistic Action of a RAF Inhibitor and a Dual PI3K/mTOR Inhibitor in Thyroid Cancer , 2011, Clinical Cancer Research.

[132]  A. Lazar,et al.  Targeting the PI3K/mTOR Axis, Alone and in Combination with Autophagy Blockade, for the Treatment of Malignant Peripheral Nerve Sheath Tumors , 2012, Molecular Cancer Therapeutics.

[133]  M. Xing,et al.  Mutations in Critical Domains Confer the Human mTOR Gene Strong Tumorigenicity* , 2013, The Journal of Biological Chemistry.

[134]  E. Nakakura,et al.  Incomplete inhibition of phosphorylation of 4E-BP1 as a mechanism of primary resistance to ATP-competitive mTOR inhibitors , 2013, Oncogene.

[135]  Sarat Chandarlapaty,et al.  mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. , 2011, Cancer discovery.

[136]  J. Urano,et al.  Point mutations in TOR confer Rheb-independent growth in fission yeast and nutrient-independent mammalian TOR signaling in mammalian cells , 2007, Proceedings of the National Academy of Sciences.

[137]  Jung Young Lee,et al.  Mutational Analysis of AKT1, AKT2 and AKT3 Genes in Common Human Carcinomas , 2006, Oncology.

[138]  E. Kikuchi,et al.  Dual Phosphatidylinositol-3-Kinase / Mammalian Target of Rapamycin Inhibitor NVP-BEZ 235 Sensitizes Docetaxel in Castration Resistant Prostate Cancer , 2013 .

[139]  S. Kojima,et al.  Growth inhibition by NVP-BEZ235, a dual PI3K/mTOR inhibitor, in hepatocellular carcinoma cell lines. , 2011, Oncology reports.

[140]  Spyro Mousses,et al.  A transforming mutation in the pleckstrin homology domain of AKT1 in cancer , 2007, Nature.

[141]  H. Zhang,et al.  A Comparison of Ku0063794, a Dual mTORC1 and mTORC2 Inhibitor, and Temsirolimus in Preclinical Renal Cell Carcinoma Models , 2013, PloS one.

[142]  Ronald W. Davis,et al.  Superoxide anions regulate TORC1 and its ability to bind Fpr1:rapamycin complex , 2008, Proceedings of the National Academy of Sciences.

[143]  P. Lollini,et al.  NVP-BEZ235 as a New Therapeutic Option for Sarcomas , 2010, Clinical Cancer Research.

[144]  K. Flatten,et al.  Dual mTORC1/mTORC2 inhibition diminishes Akt activation and induces Puma-dependent apoptosis in lymphoid malignancies. , 2012, Blood.

[145]  Stephen McLaughlin,et al.  PIK3CA and PTEN Gene and Exon Mutation-Specific Clinicopathologic and Molecular Associations in Colorectal Cancer , 2013, Clinical Cancer Research.

[146]  P. Lollini,et al.  High metastatic efficiency of human sarcoma cells in Rag2/gammac double knockout mice provides a powerful test system for antimetastatic targeted therapy. , 2010, European journal of cancer.

[147]  C. Thompson,et al.  An activated mTOR mutant supports growth factor-independent, nutrient-dependent cell survival , 2004, Oncogene.

[148]  R. Loewith,et al.  Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive , 2004, Nature Cell Biology.

[149]  Jing Yuan,et al.  Interfering with Resistance to Smoothened Antagonists by Inhibition of the PI3K Pathway in Medulloblastoma , 2010, Science Translational Medicine.

[150]  D. Dittmer,et al.  Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine proliferative loops in PI3K/Akt/mTOR-addicted lymphomas. , 2010, Blood.

[151]  D. Cho,et al.  mTOR inhibitors in renal cell carcinoma. , 2011, Therapy.

[152]  Yan Luo,et al.  Updates of mTOR inhibitors. , 2010, Anti-cancer agents in medicinal chemistry.

[153]  R. Iglesias-Bartolome,et al.  Exploiting the mTOR paradox for disease prevention , 2012, Oncotarget.

[154]  Max S Wicha,et al.  Cancer stem cells: an old idea--a paradigm shift. , 2006, Cancer research.

[155]  D. Proia,et al.  Targeting KRAS-Mutant Non–Small Cell Lung Cancer with the Hsp90 Inhibitor Ganetespib , 2012, Molecular Cancer Therapeutics.

[156]  S. Fulda,et al.  Targeting Aberrant PI3K/Akt Activation by PI103 Restores Sensitivity to TRAIL-Induced Apoptosis in Neuroblastoma , 2011, Clinical Cancer Research.

[157]  D. Guertin,et al.  Rictor, a Novel Binding Partner of mTOR, Defines a Rapamycin-Insensitive and Raptor-Independent Pathway that Regulates the Cytoskeleton , 2004, Current Biology.

[158]  Lei Wang,et al.  Significance of mTOR Signaling and Its Inhibitor Against Cancer Stem-Like Cells in Colorectal Cancer , 2013, Annals of Surgical Oncology.

[159]  Makoto M Taketo,et al.  Colonic polyposis caused by mTOR-mediated chromosomal instability in Apc+/Δ716 Cdx2+/− compound mutant mice , 2003, Nature Genetics.

[160]  E. Lalli,et al.  Efficacy of the novel dual PI3-kinase/mTOR inhibitor NVP-BEZ235 in a preclinical model of adrenocortical carcinoma , 2012, Molecular and Cellular Endocrinology.

[161]  K. Shokat,et al.  Dual inhibition of PI3Kalpha and mTOR as an alternative treatment for Kaposi's sarcoma. , 2008, Cancer research.

[162]  Steven Zheng,et al.  mTOR-independent 4E-BP1 phosphorylation is associated with cancer resistance to mTOR kinase inhibitors , 2012, Cell cycle.

[163]  Qiang Yu,et al.  PDK1 signaling toward PLK1-MYC activation confers oncogenic transformation, tumor-initiating cell activation, and resistance to mTOR-targeted therapy. , 2013, Cancer discovery.

[164]  A. Y. Lu,et al.  Pharmacogenetics, Pharmacogenomics, and Individualized Medicine , 2011, Pharmacological Reviews.

[165]  Jing Chen,et al.  Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor , 2010, Nature Medicine.

[166]  Kevin Curran,et al.  Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. , 2009, Cancer research.

[167]  Richie Soong,et al.  Pharmacologic synergy between dual phosphoinositide-3-kinase and mammalian target of rapamycin inhibition and 5-Fluorouracil in PIK3CA mutant gastric cancer cells , 2012, Cancer biology & therapy.

[168]  D. Sherris,et al.  The novel Akt inhibitor Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer , 2009, British Journal of Cancer.

[169]  G. Devroede,et al.  Colonic hamartomas in tuberous sclerosis. , 1988, Gastroenterology.

[170]  Lisa L. Smith,et al.  AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. , 2010, Cancer research.

[171]  S. Signoretti,et al.  The Efficacy of the Novel Dual PI3-Kinase/mTOR Inhibitor NVP-BEZ235 Compared with Rapamycin in Renal Cell Carcinoma , 2010, Clinical Cancer Research.

[172]  Suzanne F. Jones,et al.  Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[173]  R. Figlin,et al.  300 A COMPARISON OF KU0063794, A DUAL MTORC1 AND MTORC2 INHIBITOR, AND TEMSIROLIMUS IN PRECLINICAL RENAL CELL CARCINOMA MODELS , 2012 .

[174]  C. Kuo,et al.  Augmented Wnt Signaling in a Mammalian Model of Accelerated Aging , 2007, Science.

[175]  Ralph Weissleder,et al.  Effective Use of PI3K and MEK Inhibitors to Treat Mutant K-Ras G12D and PIK3CA H1047R Murine Lung Cancers , 2008, Nature Medicine.

[176]  H. Wakimoto,et al.  A dual PI3K/mTOR inhibitor, PI-103, cooperates with stem cell-delivered TRAIL in experimental glioma models. , 2011, Cancer research.

[177]  E. Giang,et al.  Radiosensitization of prostate cancer cells by the dual PI3K/mTOR inhibitor BEZ235 under normoxic and hypoxic conditions. , 2013, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[178]  D. Sherris,et al.  The TORC1/TORC2 inhibitor, Palomid 529, reduces tumor growth and sensitizes to docetaxel and cisplatin in aggressive and hormone-refractory prostate cancer cells. , 2011, Endocrine-related cancer.

[179]  Cristina M Rondinone,et al.  Mammalian target of rapamycin regulates IRS-1 serine 307 phosphorylation. , 2004, Biochemical and biophysical research communications.

[180]  K. Shokat,et al.  Characterization of structurally distinct, isoform-selective phosphoinositide 3′-kinase inhibitors in combination with radiation in the treatment of glioblastoma , 2008, Molecular Cancer Therapeutics.