Review of PI3K/mTOR inhibitors entering clinical trials to treat triple negative breast cancers

Recent Patents on Anti-Cancer Drug Discovery

Volumn 11, Issue 3, 2016, Pages 283-296

  Fouqué, Amélie ^a   Jean, Mickael ^b   van de Weghe, Pierre ^b   Legembre, Patrick ^a  

^a CENTRE EUGÈNE MARQUIS   (France)

^b UNIVERSITÉ DE RENNES 1   (France)

Author keywords

Breast cancer; Clinical trial; mTOR; PI3K; Therapy; Triple negative breast cancer

Indexed keywords

ANTHRACYCLINE; AZD 8055; COUMARIN; CYCLIN D1; CYCLOPHOSPHAMIDE; DACTOLISIB; DOCETAXEL; EPIDERMAL GROWTH FACTOR RECEPTOR 2; EVEROLIMUS; FK 506 BINDING PROTEIN; FLUOROURACIL; G PROTEIN COUPLED RECEPTOR; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; MACROLIDE; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; METHOTREXATE DERIVATIVE; PACLITAXEL; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PROTEIN KINASE B; PROTEIN KINASE B INHIBITOR; RAPAMYCIN; SAPANISERTIB; SOMATOMEDIN C; TEMSIROLIMUS; TYROSINE KINASE RECEPTOR; UNINDEXED DRUG; VASCULOTROPIN A; VOXTALISIB; ZOTAROLIMUS; ANTINEOPLASTIC AGENT; MTOR PROTEIN, HUMAN; PROTEIN KINASE INHIBITOR; TARGET OF RAPAMYCIN KINASE;

ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER CHEMOTHERAPY; CANCER SURVIVAL; CELL CYCLE G1 PHASE; CELL MIGRATION; CELL PROLIFERATION; CLINICAL TRIAL (TOPIC); COMPETITIVE INHIBITION; DISEASE DURATION; DRUG EFFICACY; ESTROGEN RECEPTOR POSITIVE BREAST CANCER; GENE AMPLIFICATION; GENE EXPRESSION; HUMAN; INFLAMMATION; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; RECEPTOR DOWN REGULATION; RECURRENT DISEASE; SIGNAL TRANSDUCTION; TRIPLE NEGATIVE BREAST CANCER; TUMOR GROWTH; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMICAL STRUCTURE; CHEMISTRY; DRUG DEVELOPMENT; DRUG EFFECTS; ENZYMOLOGY; FEMALE; METABOLISM; MOLECULARLY TARGETED THERAPY; PATHOLOGY; STRUCTURE ACTIVITY RELATION; TRIPLE NEGATIVE BREAST NEOPLASMS;

ANIMALS; ANTINEOPLASTIC AGENTS; CLINICAL TRIALS AS TOPIC; DRUG DISCOVERY; FEMALE; HUMANS; MOLECULAR STRUCTURE; MOLECULAR TARGETED THERAPY; PHOSPHATIDYLINOSITOL 3-KINASE; PROTEIN KINASE INHIBITORS; SIGNAL TRANSDUCTION; STRUCTURE-ACTIVITY RELATIONSHIP; TOR SERINE-THREONINE KINASES; TRIPLE NEGATIVE BREAST NEOPLASMS;

EID: 84983781386     PISSN: 15748928     EISSN: 22123970     Source Type: Journal    
DOI: 10.2174/1574892811666160519113731     Document Type: Article

References (155)

1. Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 2010; 46(4): 765-81.
2. Mariotto AB, Yabroff KR, Shao Y, Feuer EJ, Brown ML. Projections of the cost of cancer care in the United States: 2010-2020. J Natl Cancer Inst 2011; 103(2): 117-28.
3. Sotiriou C, Pusztai L. Gene-expression signatures in breast cancer. N Engl J Med 2009; 360(8): 790-800.
4. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature 2000; 406(6797): 747-52.
5. Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, et al. A multigene assay to predict recurrence of tamoxifen-treated, nodenegative breast cancer. N Engl J Med 2004; 351(27): 2817-26.
6. Chin K, DeVries S, Fridlyand J, Spellman PT, Roydasgupta R, Kuo WL, et al. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell 2006; 10(6): 529-41.
7. Foulkes WD, Stefansson IM, Chappuis PO, Begin LR, Goffin JR, Wong N, et al. Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 2003; 95(19): 1482-5.
8. Koboldt DC, Fulton RS, McLellan MD, Schmidt H, Kalicki-Veizer J, McMichael JF. Comprehensive molecular portraits of human breast tumours. Nature 2012; 490(7418): 61-70.
9. Miller TW, Rexer BN, Garrett JT, Arteaga CL. Mutations in the phosphatidylinositol 3-kinase pathway: Role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res 2011; 13(6): 224.
10. Burke, G., Lane, H., Linnartz RR, Versace, R.W. Combinations of therapeutic agents for treating cancer. WO2008124252 (2008).
11. Menear, K., Smith, G.C.M., Malagu, K., Duggan, H.M.E., Martin, N.M.B., Leroux, F.G.M. Pyrido-, pyrazo-and pyrimido-pyrimidine derivatives as mTOR inhibitors. US8435985 (2013).
12. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med 2010; 363(20): 1938-48.
13. Robblee J, Collins BE, Kaundinya G, Bosques CJ. Methods related to bevacizumab WO2014181586 (2014).
14. Liedtke C, Mazouni C, Hess KR, Andre F, Tordai A, Mejia JA, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 2008; 26(8): 1275-81.
15. Tan DS, Marchio C, Jones RL, Savage K, Smith IE, Dowsett M, et al. Triple negative breast cancer: Molecular profiling and prognostic impact in adjuvant anthracycline-treated patients. Breast Cancer Res Treat 2008; 111(1): 27-44.
16. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006; 7(8): 606-19.
17. Brazzatti JA, Klingler-Hoffmann M, Haylock-Jacobs S, Harata-Lee Y, Niu M, Higgins MD, et al. Differential roles for the p101 and p84 regulatory subunits of PI3Kgamma in tumor growth and metastasis. Oncogene 2012; 31(18): 2350-61.
18. Vadas O, Burke JE, Zhang X, Berndt A, Williams RL. Structural basis for activation and inhibition of class I phosphoinositide 3-kinases. Sci Signaling 2011; 4(195).
19. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD. Cellular function of phosphoinositide 3-kinases: Implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol 2001; 17: 615-75.
20. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004; 304(5670): 554.
21. Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res 2005; 65(7): 2554-9.
22. Jarvis LM. PI3K At the clinical crossroads. Chem Eng News 2011; 89: 15-9.
23. Shuttleworth SJ, Silva FA, Cecil AR, Tomassi CD, Hill TJ, Raynaud FI, et al. Progress in the preclinical discovery and clinical development of class I and dual class I/IV phosphoinositide 3-kinase (PI3K) inhibitors. Curr Med Chem 2011; 18(18): 2686-714.
24. Hirsch E, Katanaev VL, Garlanda C, Azzolino O, Pirola L, Silengo L, et al. Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation. Science 2000; 287(5455): 1049-53.
25. Rommel C, Camps M, Ji H. PI3K delta and PI3K gamma: Partners in crime in inflammation in rheumatoid arthritis and beyond? Nat Rev Immunol 2007; 7(3): 191-201.
26. Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, Hemmings BA, et al. The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci USA 1998; 95(23): 13513-8.
27. Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 1998; 95(1): 29-39.
28. Gewinner C, Wang ZC, Richardson A, Teruya-Feldstein J, Etemadmoghadam D, Bowtell D, et al. Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling. Cancer Cell 2009; 16(2): 115-25.
29. Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, et al. Characterization of a 3-phosphoinositidedependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 1997; 7(4): 261-9.
30. Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 2006; 11(6): 859-71.
31. Gao X, Zhang Y, Arrazola P, Hino O, Kobayashi T, Yeung RS, et al. Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat Cell Biol 2002; 4(9): 699-704.
32. 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(9): 648-57.
33. Tee AR, Fingar DC, Manning BD, Kwiatkowski DJ, Cantley LC, Blenis J. Tuberous sclerosis complex-1 and-2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc Natl Acad Sci USA 2002; 99(21): 13571-6.
34. Inoki K, Li Y, Xu T, Guan KL. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 2003; 17(15): 1829-34.
35. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005; 307(5712): 1098-101.
36. Manning BD, Logsdon MN, Lipovsky AI, Abbott D, Kwiatkowski DJ, Cantley LC. Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2. Genes Dev 2005; 19(15): 1773-8.
37. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006; 66(3): 1500-8.
38. Shah OJ, Wang Z, Hunter T. Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr Biol 2004; 14(18): 1650-6.
39. Tremblay F, Marette A. Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells. J Biol Chem 2001; 276(41): 38052-60.
40. Vezina C, Kudelski A, Sehgal SN. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J. Antibiot 1975; 28(10): 721-6.
41. Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS, et al. A mammalian protein targeted by G1-arresting rapamycinreceptor complex. Nature 1994; 369(6483): 756-8.
42. Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH. RAFT1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 1994; 78(1): 35-43.
43. Chiu MI, Katz H, Berlin V. RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. Proc Natl Acad Sci USA 1994; 91(26): 12574-8.
44. Populo H, Lopes JM, Soares P. The mTOR signalling pathway in human cancer. Int J Mol Sci 2012; 13(2): 1886-918.
45. Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med 2006; 355(13): 1345-56.
46. 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): 1231-41.
47. Grunt TW, Mariani GL. Novel approaches for molecular targeted therapy of breast cancer: Interfering with PI3K/AKT/mTOR signaling. Curr Cancer Drug Targets 2013; 13(2): 188-204.
48. Mihaylova MM, Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 2011; 13(9): 1016-23.
49. Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, et al. TSC2 integrates Wnt and energy signals via a coordinated phos phorylation by AMPK and GSK3 to regulate cell growth. Cell 2006; 126(5): 955-68.
50. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 2008; 30(2): 214-26.
51. Jewell JL, Guan KL. Nutrient signaling to mTOR and cell growth. Trends Biochem Sci 2013; 38(5): 233-42.
52. Garami A, Zwartkruis FJ, Nobukuni T, Joaquin M, Roccio M, Stocker H, et al. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell 2003; 11(6): 1457-66.
53. Bar-Peled L, Schweitzer LD, Zoncu R, Sabatini DM. Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell 2012; 150(6): 1196-208.
54. Kang SA, Pacold ME, Cervantes CL, Lim D, Lou HJ, Ottina K, et al. mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin. Science 2013; 341(6144): 1236566.
55. Danial NN. BAD: Undertaker by night, candyman by day. Oncogene 2008; 27 (Suppl 1): S53-70.
56. Datta SR, Brunet A, Greenberg ME. Cellular survival: A play in three Akts. Genes & Dev 1999; 13(22): 2905-27.
57. Birkenkamp KU, Coffer PJ. Regulation of cell survival and proliferation by the FOXO (Forkhead box, class O) subfamily of Forkhead transcription factors. Biochem Soc Trans 2003; 31(Pt 1): 292-7.
58. Ogawara Y, Kishishita S, Obata T, Isazawa Y, Suzuki T, Tanaka K, et al. Akt enhances Mdm2-mediated ubiquitination and degradation of p53. J Biol Chem 2002; 277(24): 21843-50.
59. Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature 2001; 411(6835): 355-65.
60. Diehl JA, Cheng M, Roussel MF, Sherr CJ. Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 1998; 12(22): 3499-511.
61. Alt JR, Cleveland JL, Hannink M, Diehl JA. Phosphorylationdependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation. Genes Dev 2000; 14(24): 3102-14.
62. Kops GJ, de Ruiter ND, De Vries-Smits AM, Powell DR, Bos JL, Burgering BM. Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature 1999; 398(6728): 630-4.
63. Rena G, Guo S, Cichy SC, Unterman TG, Cohen P. Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B. J Biol Chem 1999; 274(24): 17179-83.
64. Burgering BM, Kops GJ. Cell cycle and death control: Long live Forkheads. Trends Biochem Sci 2002; 27(7): 352-60.
65. Burgering BM, Medema RH. Decisions on life and death: FOXO Forkhead transcription factors are in command when PKB/Akt is off duty. J Leukoc Biol 2003; 73(6): 689-701.
66. Stahl M, Dijkers PF, Kops GJ, Lens SM, Coffer PJ, Burgering BM, et al. The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2. J Immunol 2002; 168(10): 5024-31.
67. Shin I, Yakes FM, Rojo F, Shin NY, Bakin AV, Baselga J, et al. PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Nat Med 2002; 8(10): 1145-52.
68. Li Y, Dowbenko D, Lasky LA. AKT/PKB phosphorylation of p21Cip/WAF1 enhances protein stability of p21Cip/WAF1 and promotes cell survival. J Biol Chem 2002; 277(13): 11352-61.
69. Mayo LD, Donner DB. A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci USA 2001; 98(20): 11598-603.
70. Zhou BP, Liao Y, Xia W, Zou Y, Spohn B, Hung MC. HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat Cell Biol 2001; 3(11): 973-82.
71. Weinberg RA. The retinoblastoma protein and cell cycle control. Cell 1995; 81(3): 323-30.
72. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012; 149(2): 274-93.
73. Cain RJ, Ridley AJ. Phosphoinositide 3-kinases in cell migration. Biol Cell 2009; 101(1): 13-29.
74. Merlot S, Firtel RA. Leading the way: Directional sensing through phosphatidylinositol 3-kinase and other signaling pathways. J Cell Sci 2003; 116(Pt 17): 3471-8.
75. Procko E, McColl SR. Leukocytes on the move with phosphoinositide 3-kinase and its downstream effectors. BioEssays: News and Bioessays 2005; 27(2): 153-63.
76. Ward SG. Do phosphoinositide 3-kinases direct lymphocyte navigation? Trends Immunol 2004; 25(2): 67-74.
77. Srinivasan S, Wang F, Glavas S, Ott A, Hofmann F, Aktories K, et al. Rac and Cdc42 play distinct roles in regulating PI(3,4,5)P3 and polarity during neutrophil chemotaxis. J Cell Biol 2003; 160(3): 375-85.
78. Ali K, Bilancio A, Thomas M, Pearce W, Gilfillan AM, Tkaczyk C, et al. Essential role for the p110delta phosphoinositide 3-kinase in the allergic response. Nature 2004; 431(7011): 1007-11.
79. Graupera M, Guillermet-Guibert J, Foukas LC, Phng LK, Cain RJ, Salpekar A, et al. Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration. Nature 2008; 453(7195): 662-6.
80. Malleter M, Tauzin S, Bessede A, Castellano R, Goubard A, Godey F, et al. CD95L cell surface cleavage triggers a prometastatic signaling pathway in triple-negative breast cancer. Cancer Res 2013; 73(22): 6711-21.
81. Jean, M., Fouque, A., Legembre, P., Van, D.W.P. New PI3K/AKT/MTOR inhibitors and pharmaceutical uses thereof. WO2015044229 (2015).
82. Legembre, P., Malleter, M., Tauzin, S., Godey, F., Leveque, J. Methods for predicting and preventing metastasis in triple negative breast cancers. WO2014118317 (2014).
83. Legembre, P., Segui, B., Levade, T., Micheau, O. Methods and pharmaceutical compositions for preventing or reducing metastatic dissemination. WO2015104284 (2015).
84. Xue G, Hemmings BA. PKB/Akt-dependent regulation of cell motility. J Natl Cancer Inst 2013; 105(6): 393-404.
85. Enomoto A, Murakami H, Asai N, Morone N, Watanabe T, Kawai K, et al. Akt/PKB regulates actin organization and cell motility via Girdin/APE. Developmental cell 2005; 9(3): 389-402.
86. Elloul S, Kedrin D, Knoblauch NW, Beck AH, Toker A. The adherens junction protein afadin is an AKT substrate that regulates breast cancer cell migration. Mol Cancer Res 2014; 12(3): 464-76.
87. Manser E, Leung T, Salihuddin H, Zhao ZS, Lim L. A brain serine/ threonine protein kinase activated by Cdc42 and Rac1. Nature 1994; 367(6458): 40-6.
88. Edwards DC, Sanders LC, Bokoch GM, Gill GN. Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics. Nat cell Bio 1999; 1(5): 253-9.
89. King CC, Gardiner EM, Zenke FT, Bohl BP, Newton AC, Hemmings BA, et al. p21-activated kinase (PAK1) is phosphorylated and activated by 3-phosphoinositide-dependent kinase-1 (PDK1). J Biol Chem 2000; 275(52): 41201-9.
90. Tsakiridis T, Taha C, Grinstein S, Klip A. Insulin activates a p21-activated kinase in muscle cells via phosphatidylinositol 3-kinase. J Biol Chem 1996; 271(33): 19664-7.
91. di Blasio L, Gagliardi PA, Puliafito A, Sessa R, Seano G, Bussolino F, et al. PDK1 regulates focal adhesion disassembly by modulating endocytosis of alphavbeta3 integrin. J Cell Sci 2015; 128(5): 863-77.
92. Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004; 6(11): 1122-8.
93. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, 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): 1296-302.
94. Hernandez-Negrete I, Carretero-Ortega J, Rosenfeldt H, Hernandez-Garcia R, Calderon-Salinas JV, Reyes-Cruz G, et al. P-Rex1 links mammalian target of rapamycin signaling to Rac activation and cell migration. J Biol Chem 2007; 282(32): 23708-15.
95. Masri J, Bernath A, Martin J, Jo OD, Vartanian R, Funk A, et al. mTORC2 activity is elevated in gliomas and promotes growth and cell motility via overexpression of rictor. Cancer Res 2007; 67(24): 11712-20.
96. Yuan R, Kay A, Berg WJ, Lebwohl D. Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy. J Hematol Oncol 2009; 2: 45.
97. Yang H, Rudge DG, Koos JD, Vaidialingam B, Yang HJ, Pavletich NP. mTOR kinase structure, mechanism and regulation. Nature 2013; 497(7448): 217-23.
98. Huang, W.S., River, V.M., Clackson, T.P., Shakespeare, W.C., Squillace, R.M., Gozgit, J.M. Methods and compositions for treating cancer. WO2011053938 (2011).
99. Dukart, G., Gibbons, J.J., Berkenblit, A., Feingold, J.M. Antitumor activity of temsirolimus in papillary renal cell cancer. WO2008124125 (2008).
100. Moore, L. Antineoplastic combinations of temsirolimus and sunitinib malate. US20070105887 (2007).
101. Wolff AC, Lazar AA, Bondarenko I, Garin AM, Brincat S, Chow L, et al. Randomized Phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer. J Clin Oncol 2013; 31(2): 195-202.
102. Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 2008; 118(9): 3065-74.
103. Rui L, Fisher TL, Thomas J, White MF. Regulation of insulin/ insulin-like growth factor-1 signaling by proteasome-mediated degradation of insulin receptor substrate-2. J Biol Chem 2001; 276(43): 40362-7.
104. Treins C, Warne PH, Magnuson MA, Pende M, Downward J. Rictor is a novel target of p70 S6 kinase-1. Oncogene 2010; 29(7): 1003-16.
105. Cloughesy TF, Yoshimoto K, Nghiemphu P, Brown K, Dang J, Zhu S, et al. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med 2008; 5(1): e8.
106. Barr, S., Buck, E.A., Epstein, D.M., Gokhale, P.C., Miglarese, M.R. Combination anti-cancer therapy. WO2011112666 (2011).
107. Treilleux, I., Bachelot, T., Romancer-Cherifi, M. Lkb1 as predictive marker of everolimus efficacy in breast cancer. WO2014001562 (2014).
108. Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Makela TP, et al. Complexes between the LKB1 tumor suppressor, STRAD alpha/ beta and MO25 alpha/beta are upstream kinases in the AMPactivated protein kinase cascade. J Biol 2003; 2(4): 28.
109. Hong SP, Leiper FC, Woods A, Carling D, Carlson M. Activation of yeast Snf1 and mammalian AMP-activated protein kinase by upstream kinases. Proc Natl Acad Sci USA 2003; 100(15): 8839-43.
110. Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG, Neumann D, et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr Biol 2003; 13(22): 2004-8.
111. Corradetti MN, Inoki K, Bardeesy N, DePinho RA, Guan KL. Regulation of the TSC pathway by LKB1: Evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes Dev 2004; 18(13): 1533-8.
112. Chresta CM, Davies BR, Hickson I, Harding T, Cosulich S, Critchlow SE, 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. Cancer Res 2010; 70(1): 288-98.
113. Asahina H, Nokihara H, Yamamoto N, Yamada Y, Tamura Y, Honda K, et al. Safety and tolerability of AZD8055 in Japanese patients with advanced solid tumors; A dose-finding Phase I study. Invest New Drugs 2013; 31(3): 677-84.
114. Naing A, Aghajanian C, Raymond E, Olmos D, Schwartz G, Oelmann E, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma. Br J Cancer 2012; 107(7): 1093-9.
115. Zhang H, Dou J, Yu Y, Zhao Y, Fan Y, Cheng J, et al. mTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling. Apoptosis 2015; 20(1): 50-62.
116. Liu Q, Thoreen C, Wang J, Sabatini D, Gray NS. mTOR mediated anti-cancer drug discovery. Drug Discov Today Ther Strateg 2009; 6(2): 47-55.
117. Kushner, P.J., Myles, D.C., Harmon, C.L., Gallagher, L.C.H. Benzopyran compounds, compositions and uses thereof. WO2013090921 (2013).
118. Hsieh AC, Liu Y, Edlind MP, Ingolia NT, Janes MR, Sher A, et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 2012; 485(7396): 55-61.
119. Pike KG, Malagu K, Hummersone MG, Menear KA, Duggan HM, Gomez S, et al. Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: The discovery of AZD8055 and AZD2014. Bioorg Med Chem Lett 2013; 23(5): 1212-6.
120. Kaur, B., Wojton, J. Materials and methods useful for treating glioblastoma. WO2014078522 (2014).
121. Hancox U, Cosulich S, Hanson L, Trigwell C, Lenaghan C, Ellston R, et al. Inhibition of PI3Kbeta signaling with AZD8186 inhibits growth of PTEN-deficient breast and prostate tumors alone and in combination with docetaxel. Mol Cancer Ther 2015; 14(1): 48-58.
122. Powles T, Wheater M, Din O, Geldart T, Boleti E, Stockdale A, et al. A randomised Phase 2 study of AZD2014 versus everolimus in patients with VEGF-refractory metastatic clear cell renal cancer. Eur Urol 2015; 69(3): 450-6.
123. Basu B, Dean E, Puglisi M, Greystoke A, Ong M, Burke W, et al. First-in-human pharmacokinetic and pharmacodynamic study of the dual m-TORC 1/2 inhibitor AZD2014. Clin Cancer Res 2015; 21(15): 3412-9.
124. Takai H, Wang RC, Takai KK, Yang H, de Lange T. Tel2 regulates the stability of PI3K-related protein kinases. Cell 2007; 131(7): 1248-59.
125. Fouque A, Delalande O, Jean M, Castellano R, Josselin E, Malleter M, et al. A novel covalent mTOR inhibitor, DHM25, shows in vivo antitumor activity against triple-negative breast cancer cells. J Med Chem 2015; 58(16): 6559-73.
126. Yu P, Laird AD, Du X, Wu J, Won KA, Yamaguchi K, et al. Characterization of the activity of the PI3K/mTOR inhibitor XL765 (SAR245409) in tumor models with diverse genetic alterations affecting the PI3K pathway. Mol Cancer Ther 2014; 13(5): 1078-91.
127. Papadopoulos KP, Tabernero J, Markman B, Patnaik A, Tolcher AW, Baselga J, et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245409 (XL765), a novel, orally administered PI3K/mTOR inhibitor in patients with advanced solid tumors. Clin Cancer Res 2014; 20(9): 2445-56.
128. Papadopoulos KP, Egile C, Ruiz-Soto R, Jiang J, Shi W, Bentzien F, et al. Efficacy, safety, pharmacokinetics and pharmacodynamics of SAR245409 (voxtalisib, XL765), an orally administered phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor: A Phase 1 expansion cohort in patients with relapsed or refractory lymphoma. Leuk Lymphoma 2015; 56(6): 1763-70.
129. Hirawat, S., Massacesi, C. Dosage regimen for a PI-3 kinase inhibitor. WO2013173283 (2013).
130. Burger MT, Pecchi S, Wagman A, Ni ZJ, Knapp M, Hendrickson T, et al. Identification of NVP-BKM120 as a potent, selective, orally bioavailable class I PI3 kinase inhibitor for treating cancer. ACS Med Chem Lett 2011; 2(10): 774-9.
131. Bendell JC, Rodon J, Burris HA, de Jonge M, Verweij J, Birle D, et al. Phase I, dose-escalation study of BKM120, an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol 2012; 30(3): 282-90.
132. Rodon J, Brana I, Siu LL, De Jonge MJ, Homji N, Mills D, et al. Phase I dose-escalation and-expansion study of buparlisib (BKM120), an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. Invest New Drugs 2014; 32(4): 670-81.
133. Baselga, J., Scaltriti, M. Combinations of a PI3K / Akt inhibitor compound with an HER3/EGFR inhibitor compound and use thereof in the treatment of a hyperproliferative disorder. WO2014089570 (2014).
134. Belvin, M., Friedman, L., Sampath, D., Wallin, J. Mutant selectivity and combinations of a phosphoinositide 3 kinase inhibitor compound and chemotherapeutic agents for the treatment of cancer. WO2013182668 (2013).
135. Wallin JJ, Guan J, Prior WW, Lee LB, Berry L, Belmont LD, et al. GDC-0941, a novel class I selective PI3K inhibitor, enhances the efficacy of docetaxel in human breast cancer models by increasing cell death in vitro and in vivo. Clin Cancer Res 2012; 18(14): 3901-11.
136. Folkes AJ, Ahmadi K, Alderton WK, Alix S, Baker SJ, Box G, et al. The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J Med Chem 2008; 51(18): 5522-32.
137. Tao JJ, Castel P, Radosevic-Robin N, Elkabets M, Auricchio N, Aceto N, et al. Antagonism of EGFR and HER3 enhances the response to inhibitors of the PI3K-Akt pathway in triple-negative breast cancer. Sci Signal 2014; 7(318): ra29.
138. Sarker D, Ang JE, Baird R, Kristeleit R, Shah K, Moreno V, et al. First-in-human Phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in pa tients with advanced solid tumors. Clin Cancer Res 2015; 21(1): 77-86.
139. Hausman, D.F., Jimeno, A., Peterson, S. Methods for treating oncovirus positive cancers. WO2012118978 (2012).
140. Shapiro GI, Bell-McGuinn KM, Molina JR, Bendell J, Spicer J, Kwak EL, et al. First-in-human study of PF-05212384 (PKI-587), a small-molecule, intravenous, dual inhibitor of PI3K and mTOR in patients with advanced cancer. Clin Cancer Res 2015; 21(8): 1888-95.
141. Venkatesan AM, Dehnhardt CM, Delos Santos E, Chen Z, Dos Santos O, Ayral-Kaloustian S, et al. Bis(morpholino-1,3,5-triazine) derivatives: Potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: Discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor. J Med Chem 2010; 53(6): 2636-45.
142. Yuan J, Mehta PP, Yin MJ, Sun S, Zou A, Chen J, et al. PF-04691502, a potent and selective oral inhibitor of PI3K and mTOR kinases with antitumor activity. Mol Cancer Ther 2011; 10(11): 2189-99.
143. Bonnevaux, H., Garcia-Echeverria, C., Virone-Oddos, A. Antitumoral composition comprising a PI3kbeta-selective inhibitor and a PI3kalpha-selective inhibitor. WO2014161938 (2014).
144. Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, 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. Mol Cancer Ther 2008; 7(7): 1851-63.
145. Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 2011; 121(7): 2750-67.
146. Furet P, Guagnano V, Fairhurst RA, Imbach-Weese P, Bruce I, Knapp M, et al. Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation. Bioorg Med Chem Lett 2013; 23(13): 3741-8.
147. Juric D, Castel P, Griffith M, Griffith OL, Won HH, Ellis H, et al. Convergent loss of PTEN leads to clinical resistance to a PI(3)Kalpha inhibitor. Nature 2015; 518(7538): 240-4.
148. Elkabets M, Pazarentzos E, Juric D, Sheng Q, Pelossof RA, Brook S, et al. AXL mediates resistance to PI3Kalpha inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas. Cancer Cell 2015; 27(4): 533-46.
149. Duncan LJ, Seaton DA. The treatment of diabetes mellitus with metformin. Br J Clin Pract 1962; 16: 129-32.
150. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001; 108(8): 1167-74.
151. Hardie DG. Neither LKB1 nor AMPK are the direct targets of metformin. Gastroenterology 2006; 131(3): 973.
152. El-Mir MY, Nogueira V, Fontaine E, Averet N, Rigoulet M, Leverve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 2000; 275(1): 223-8.
153. Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 2000; 348 Pt 3: 607-14.
154. Wang DS, Jonker JW, Kato Y, Kusuhara H, Schinkel AH, Sugiyama Y. Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J Pharmacol Exp Ther 2002; 302(2): 510-5.
155. Yu Y, Savage RE, Eathiraj S, Meade J, Wick MJ, Hall T, et al. Targeting AKT1-E17K and the PI3K/AKT pathway with an allosteric AKT inhibitor, ARQ 092. PLoS One 2015; 10(10): e0140479.