Dual inhibition of PI3-kinase and mTOR in renal cell carcinoma

Current Cancer Drug Targets

Volumn 13, Issue 2, 2013, Pages 126-142

  Cho, Daniel C ^a   Mier, James W ^a  

^a HARVARD MEDICAL SCHOOL   (United States)

Author keywords

Everolimus; mTOR; PI3 kinase; Renal cell carcinoma; Temsirolimus; Translation

Indexed keywords

1 (1 CYANO 1 METHYLETHYL) 3 METHYL 8 (2 MORPHOLINO 8 PHENYLCHROMONE; 1 (1 CYANO 1 METHYLETHYL) 3 METHYL 8 (3 QUINOLINYL) IMIDAZO [4, 5 C] QUINOLIN 2 (1H, 3H) ONE; 1 (1 CYANO 1 METHYLETHYL) 3 METHYL 8 (3 QUINOLINYL)IMIDAZO[4,5 C]QUINOLIN 2(1H,3H) ONE; 2 MORPHOLINO 8 PHENYLCHROMONE; 4 DIALLYLAMINOMETHYLENE 1, 3, 4, 7, 10, 11, 12, 13, 14, 15, 16, 17 DODECAHYDRO 6 HYDROXY 1 METHOXYMETHYL 10, 13 DIMETHYL 3, 7, 17 TRIOXO 2 OXACYCLOPENTA [A] PHENANTHREN 11 YL ACETATE; 4 DIALLYLAMINOMETHYLENE 1,3,4,7,10,11,12,13,14,15,16,17 DODECAHYDRO 6 HYDROXY 1 METHOXYMETHYL 10,13 DIMETHYL 3,7,17 TRIOXO 2 OXACYCLOPENTA[A]PHENANTHREN 11 YL ACETATE; [1 (4 OXO 8 PHENYL 4H 1 BENZOPYRAN 2 YL) MORPHOLINIO] METHOXYSUCCINYLARGINYLGLYCYLASPARTYLSERINE ACETATE; [1 (4 OXO 8 PHENYL 4H 1 BENZOPYRAN 2 YL)MORPHOLINIO]METHOXYSUCCINYLARGINYLGLYCYLASPARTYLSERINE ACETATE; ALPHA1 INTERFERON; BAY 806946; BUPARLISIB; BYL 179; COPANLISIB; EVEROLIMUS; GDC 941; GDC 980; GSK 2126458; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INK 1117; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; OXA 01; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PKI 179; PKI 587; PLACEBO; PWT 33579; RAPAMYCIN; SB 2343; SORAFENIB; STEROL REGULATORY ELEMENT BINDING PROTEIN; SUNITINIB; TEMSIROLIMUS; UNCLASSIFIED DRUG; UNINDEXED DRUG; XL 147; XL 765;

ANGIOGENESIS; ARTICLE; CANCER GROWTH; CANCER SURVIVAL; CELL PROLIFERATION; DOWNSTREAM PROCESSING; GENE MUTATION; HUMAN; KIDNEY CARCINOMA; LIPOGENESIS; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; RANDOMIZED CONTROLLED TRIAL (TOPIC); RNA TRANSLATION; TUMOR SUPPRESSOR GENE;

CARCINOMA, RENAL CELL; CELL DIVISION; CLINICAL TRIALS AS TOPIC; ENZYME ACTIVATION; HUMANS; KIDNEY NEOPLASMS; NEOVASCULARIZATION, PATHOLOGIC; PHOSPHATIDYLINOSITOL 3-KINASES; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

EID: 84876848578     PISSN: 15680096     EISSN: 18735576     Source Type: Journal    
DOI: 10.2174/1568009611313020003     Document Type: Article

References (142)

1. Bunney, T. D.; Katan, M. Phosphoinositide signaling in cancer: beyond PI3K and PTEN. Nat. Rev. Cancer 2010, 10, 342-352.
2. Bader, A. G.; Kang, S.; Zhao, L.; Vogt, P. K. Oncogenic PI3K deregulates transcription and translation. Nat. Rev. Cancer 2005, 5, 921-929.
3. Engelman, J. A. Targeting PI3K signaling in cancer: opportunities, challenges and limitations. Nat. Rev. Cancer 2009, 9, 50-62.
4. Hennesey, B. T.; Smith, D. L.; Ram, P. T.; Lu; Y.; Mills, G. B. Exploiting the PI3K/Akt pathway for cancer drug discovery. Nat. Rev. Drug Disc. 2005, 4, 988-1004.
5. Horiguchi, A.; Oya, M.; Uchida, A.; Marumo, K.; Murai, M. Elevated Akt activation and its impact on clinicopathologic features of renal cell carcinoma. J. Urol. 2003, 169, 710-713.
6. Samuels, Y.; Wang, Z.; Bardelli, A.; Silliman, N.; Ptak, J.; Szabo, S.; Yan, H.; Gazdar, A.; Powell, S. M.; Riggins, G. J.; Willson, J. K. V.; Markowitz, S.; Kinzler, K. W.; Vogelstein, B.; Velculescu, V. E. High frequency of mutations of the PIK3CA gene in human cancer. Science 2004, 304 (5670), 554.
7. Martin-Berenjeno, I.; Vanhaesebroeck, B. PI3K regulatory subunits lose control in cancer. Cancer Cell 2009, 16, 449-450.
8. Jaiswal, B. S.; Janakiraman, V.; Kljavin, N. M.; Chaudhuri, S.; Stern, H. M.; Wang, W.; Kan, Z.; Dbouk, H. A.; Peters, B. A.; Waring, P.; Dela Vega, T.; Kenski, D. M.; Bowman, K. K.; Lorenzo, M.; Li, H.; Wu, J.; Modrusan, Z.; Stinson, J.; Eby, M.; Yue, P.; Kaminker, J. S.; de Sauvage, F. J.; Backer, J. M.; Seshagiri, S. Somatic mutations in p85-alpha promote tumorigenesis through class IA PI3K activation. Cancer Cell 2009, 16, 463-474.
9. Qian, C. N.; Furge, K. A.; Knol, J.; Huang, D.; Chen, J.; Dykema, K. J.; Kort, E. J.; Massie, A.; Khoo, S. K.; Vanden Beldt, K.; Resau, J. H.; Anema, J.; Kahnoski, R. J.; Morreau, H.; Camparo, P.; Comperat, E.; Sibony, M.; Denoux, Y.; Molinie, V.; Viellefond, A.; Eng, C.; Williams, B. O.; The, B. T. Activation of the PI3K/Akt pathway induces urothelial carcinoma of the renal pelvis: identification in human tumors and confirmation in animal models. Cancer Res. 2009, 69, 8256-8264.
10. Hollander, M. C.; Blumenthal, G. M.; Dennis, P. A. PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat. Rev. Cancer 2011, 11, 289-301.
11. Alimov, A.; Li, C.; Gizatullin, R.; Fredriksson, V.; Sundelin, B.; Klein, G.; Zabarovsky, E.; Bergerheim, U. Somatic mutation and homozygous deletion of PTEN/MMAC1 gene of 10q23 in renal cell carcinoma. Anticancer Res. 1999, 19, 3841-3846.
12. Kondo, K.; Yao, M.; Kobayashi, K.; Ota, S.; Yoshida, M.; Kaneko, S.; Baba, M.; Sakai, N.; Kishida, T.; Kawakami, S.; Uemura, H.; Nagashima, Y.; Nakatani, Y.; Hosaka, M. PTEN/MMAC1/TEP1 mutations in human primary renal cell carcinomas and renal carcinoma cell lines. Int. J. Cancer 2001, 91, 219-224.
13. Brenner, W.; Farber, G.; Herget, T.; Lehr, H. A.; Hengstler, J. G.; Thuroff, J. W. Loss of tumor suppressor protein PTEN during renal carcinogenesis. Int. J. Cancer 2002, 99, 53-57.
14. Hager, M.; Haufe, H.; Kemmerling, R.; Mikuz, G.; Kolbitsch, C.; Moser, P. L. PTEN expression in renal cell carcinoma and oncocytoma and prognosis. Pathology 2007, 39, 482-485.
15. Schultz, L.; Chaux, A.; Albadine, R.; Hicks, J.; Kim, J. J.; Allaf, M. E.; Carducci, M. A.; Rodriguez, R.; Hammers, H. J.; Argani, P.; Reuter, V. E.; Netto, G. J. Immunoexpression status and prognostic value of mTOR and hypoxia-induced pathway members in primary and metastatic renal cell carcinomas. Am. J. Surg. Path. 2011, 35, 1549-1556.
16. Hennenlotter, J.; Ohneseit, P. A.; Simon, P.; Merseburger, A. S.; Serth, J.; Kuehs, U.; Kramer, M.; Hartmann, J. T.; Stenzl, A.; Kuczyk, M. A. PTEN and p27Kip1 are not downregulated in the majority of renal cell carcinomas-implications for Akt activation. Oncol. Rep. 2008, 19, 1141-1147.
17. Merseburger, A. S.; Hennenlotter, J.; Kuehs, U.; Simon, P.; Kruck, S.; Koch, E.; Stenzy, A.; Kuczyk, M. A. Activation of PI3K is associated with reduced survival in renal cell carcinoma. Urol. Int. 2008, 80, 372-377.
18. Dahinden, C.; Ingold, B.; Wild, P.; Boysen, G.; Luu, V. D.; Montani, M.; Kristiansen, G.; Sulser, T.; Buhlmann, P.; Moch, H.; Schrami, P. Mining tissue microarray data to uncover combinations of biomarker expression patterns that improve intermediate staging and grading of clear cell renal cell cancer. Clin. Cancer Res. 2010, 16, 88-98.
19. Vadas, O.; Burke, J. E.; Zhang, X.; Berndt, A.; Williams, R. L. Structural basis for activation and inhibition of class I phosphoinositide 3-kinases. S. T.K. E. 2011, 4, 195 re2.
20. Kleber, S.; Sancho-Martinez, I.; Wiestler, B.; Beisel, A.; Gieffers, C.; Hill, O.; Thiemann, M.; Mueller, W.; Sykora, J.; Kuhn, A.; Schreglmann, N.; Letellier, E.; Zuliani, C.; Klussmann, S.; Teodorczyk, M.; Grone, H. J.; Ganten, T. M.; Sultmann, H.; Tuttenberg, J.; von Deimling, A.; Regnier-Vigouroux, A.; Herold-Mende, C.; Martin-Villalba, A. Yes and PI3K bind CD95 to signal invasion of glioblastoma. Cancer Cell 2008, 13, 2335-2348.
21. Yang, X.; Turke, A. B.; Qi, J.; Song, Y.; Rexer, B. N.; Miller, T. W.; Janne, P. A.; Arteaga, C. L.; Cantley, L. C.; Engelman, J. A.; Asara, J. M. Using tandem mass spectrometry in targeted mode to identify activators of class IA PI3K in cancer. Cancer Res. 2011, 71, 5965-5975.
22. Gunaratnam, L.; Morley, M.; Franovic, A.; de Paulsen, N.; Mekhail, K.; Parolin, D. A.; Nakamura, E.; Lorimer, I. A.; Lee, S. Hypoxia inducible factor activates the transforming growth factoralpha/ epidermal growth factor receptor growth stimulatory pathway in VHL(-/-) renal cell carcinoma cells. J. Biol. Chem. 2003, 278, 44966-44974.
23. Rodriguez-Viciana, P.; Warne, P. H.; Dhand, R.; Vanhaesebroeck, B.; Gout, I.; Fry, M. J.; Waterfield, M. D.; Downward, J. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 1994, 370, 527-532.
24. Korusu, H.; Maehama, T.; Okada, T.; Yamamoto, T.; Hoshino, S.; Fukui, Y.; Ui, M.; Hazeki, O.; Katada, T. Heterodimeric phosphoinositide 3-kinase consisting of p85 and p110beta is synergistically activated by the beta/gamma subunits of G proteins and phosphotyrosyl peptide. J. Biol. Chem. 1997, 272, 24252-24256.
25. Ping, Y. F.; Yao, X. H.; Jiang, L. T.; Yu, S. C.; Jiang, T.; Lin, M. C.; Chen, J. H.; Wang, B.; Zhang, R.; Cui, Y. H.; Qian, C.; Wang, J.; Bian, X. W. The chemokine CXCL12 and its receptor CXCR4 promote glioma stem cell-mediated VEGF production and tumour angiogenesis via PI3K/AKT signaling. J. Pathol. 2011, 224, 344-354.
26. Hudes, G.; Carducci, M.; Tomczak, P.; Dutcher, J.; Figlin, R.; Kapoor, A.; Staroslawska, E.; Sosman, J.; McDermott, D.; Bodrogi, I.; Kovacevic, Z.; Lesovoy, V.; Schmidt-Wolf, I. G.; Barbarash, O.; Gokmen, E.; O'Toole, T.; Lustgarten, S.; Moore, L.; Motzer, R. J. Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Eng. J. Med. 2007, 356, 2271-2275.
27. Motzer, R. J.; Escudier, B.; Oudard, S.; Hutson, T. E.; Porta, C.; Bracarda, S.; Grunwald, V.; Thompson, J. A.; Figlin, R. A.; Hollaender, N.; Urbanowitz, G.; Berg, W. J.; Kay, A.; Lebwohl, D.; Ravaud, A. for the RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomized, placebo-controlled phase III trial. Lancet 2008, 372, 449-456.
28. Mora, A.; Komander, D.; van Aalten, D. M. F.; Alessi, D. R. PDK1, the master regulator of AGC kinase signal transduction. Sem. Cell and Dev. Biol. 2004, 151, 161-170.
29. Masters, T. A.; Calleja, V.; Armoogum, D. A.; Marsh, R. J.; Applebee, C. J.; Laguerre, M.; Bain, A. J.; Larijani, B. Regulation of 3-phosphoinositide-dependent protein kinase 1 activity by homodimerization in live cells. S.T.K.E. 2010, 3, 145 ra78.
30. Sarbassov, D. D.; Ali, S. M.; Kim, D.-H.; Guertin, D. A.; Latek, R. R.; Erdjument-Bromage, H.; Tempst, P.; Sabatini, D. M. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 2004, 14, 1296-1302.
31. Sarbassov, D. D.; Guertin, D. A.; Ali, S M.; Sabatini, D. M. Phosphorylation and regulation of Akt/PKB by the Rictor-mTOR complex. Science 2005, 307, 1098-1101.
32. Guo, J.-P.; Coppola, D.; Cheng, J. Q. IKBKE activates Akt independent of phosphatidylinositol 3-kinase/PDK1/mTORC2 and PH domain to sustain malignant transformation. J. Biol. Chem. 2011, 286, 37389-37398.
33. Boehm, J. S.; Zhao, J. J.; Yao, J.; Kim, S. Y.; Firestein, R.; Dunn, I. F.; Sjostron, S. K.; Garraway, L. A.; Weremowicz, S.; Richardson, A. L.; Greulich, H.; Stewart, C. J.; Mulvey, L. A.; Shen, R. R.; Ambrogio, L.; Hirozane,-Kishikawa, T.; Hill, D. E.; Vidal, M.; Meyerson, M.; Grenier, J. K.; Hinkle, G.; Root, D. E.; Roberts, T. M.; Lander, E. S.; Polyak, K.; Hahn, W. C. Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell 2007, 129, 1065-1079.
34. Jacinto, E.; Facchinetti, V.; Liu, D.; Soto, N.; Wei, S.; Jung, S. Y.; Huang, Q.; Su, B. SIN1/MIP1 maintains rector-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 2006, 127, 125-137.
35. Zhao, S.; Guan, K.-L. Substrate selectivity APPLies to Akt. Cell 2008, 133, 399-400.
36. Schenck, A.; Goto-Silva, L.; Collinet, C.; Rhinn, M.; Giner, A.; Habermann, B.; Brand, M.; Zerial, M. The endosomal protein Appl1 mediates Akt substrate specificity and cell survival in vertebrate development. Cell 2008, 133, 486-497.
37. Bruhn, M. A.; Pearson, R. B.; Hannan, R. D.; Sheppard, K. E. Second AKT: The rise of SGK in cancer signaling. Growth Factors 2010, 28, 394-408.
38. Vasudevan, K. M.; Barbie, D. A.; Davies, M. A.; Babinovsky, R.; McNear, C. J.; Kim, J. J.; Hennessey, B. T.; Tseng, H.; Pochanard, P.; Kim, S. Y.; Dunn, I. F.; Schinzel, A. C.; Sandy, P.; Hoersch, S.; Sheng, Q.; Gupta, P. B.; Boehm, J. S.; Reiling, J. H.; Silver, S.; Lu, Y.; Stemke-Hale, K.; Dutta, B.; Joy, C.; Sahin, A. A.; Gonzalez-Angulo, A. M.; Lluch, A.; Rameh, L. E.; Jacks, T.; Root, D. E.; Lander, E. S.; Mills, G. B.; Hahn, W. C.; Sellers, W. R.; Garraway, L. A. Akt-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 2009, 16, 21-32.
39. Ma, X. M.; Blenis, J. Molecular mechanisms of mTOR-mediated translational control. Nat. Rev. Mol. Cell. Biol. 2009, 10, 307-318.
40. Fingar, D. C.; Blenis, J. Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene 2004, 23, 3151-3171.
41. Hsieh, A. C.; Costa, M.; Zollo, O.; Davis, C.; Feldman, M. E.; Testa, J. R.; Meyuhas, O.; Shokat, K. M.; Ruggero, D. Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E. Cancer Cell 2010, 17, 249-261.
42. Guertin, D. A.; Sabatini, D. M. An expanding role for mTOR in cancer. Trends in Mol. Med. 2005, 11, 353-361.
43. Wullschleger, S.; Loewith, R.; Hall, M. N. TOR signaling in growth and metabolism. Cell 2006, 124, 471-484.
44. Sancak, Y.; Thoreen, C. C.; Peterson, T. R.; Lindquist, R. A.; Kang, S. A.; Spooner, E.; Carr, S. A. PRAS40 is an insulinregulated inhibitor of the mTORC1 protein kinase. Mol. Cell 2007, 25, 903-915.
45. Wang, L.; Harris, T. E.; Roth, R. A.; Lawrence, J. C. PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J. Biol. Chem. 2007, 282, 20036-20044.
46. Oshiro, N.; Takahashi, R.; Yoshino, K.; Tanimura, K.; Nakashima, A.; Equchi, S.; Miyamoto T.; Takehana, K.; Avruch, J.; Kikkawa, U.; Yonezawa, K. The proline-rich Akt substrate of 40kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1. J. Biol. Chem. 2007, 282, 20329-20339.
47. Hsieh, A. C.; Ruggero, D. Targeting eukaryotic translation initiation factor 4E (eIF4E) in cancer. Clin. Cancer Res. 2010, 16, 4914-20.
48. Konicek, B. W.; Stephens, J. R.; McNulty, A. M.; Robichaud, N.; Peery, R. B.; et al. Therapeutic inhibition of MAP kinase interacting kinase blocks eukaryotic initiation factor 4E phosphorylation and suppresses outgrowth of experimental lung metastases. Cancer Res. 2011, 71, 1849-1857.
49. Cho, D. C.; Cohen, M. B.; Panka, D. J.; Collins, M.; Ghebremichael, M.; Atkins, M. B.; Signoretti, S.; Mier, J. W. The efficacy of the novel dual PI3-kinase/mTOR inhibitor NVP-BEZ235 compared with rapamycin in renal cell carcinoma. Clin. Cancer Res. 2010, 16, 3628-3638.
50. Pearce, L. R.; Komander, D.; Alessi, D. R. The nuts and bolts of AGC protein kinases. Nat. Rev. Mol. Cell. Biol. 2010, 11, 9-22.
51. Holz, M. K.; Ballif, B. A.; Gygi, S. P.; Blenis, J. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 2005, 123, 569-580.
52. Malik, R. K.; Parson, J. T. Integrin-dependent activation of the p70 ribosomal S6 kinase signaling pathway. J. Biol. Chem. 1996, 271, 29785-29791.
53. Hahn-Windgassen, A.; Nogueira, V.; Chen, C. C.; Skeen, J. E.; Sonenberg, N.; Hay, N. Akt activates the mammalian target of rapamycin by regulating cellular ATP levels and AMPK activity. J. Biol. Chem. 2005, 280, 32081-32089.
54. Stockli, J.; Davey, J. R.; Hohnen-Behrens, C.; Xu, A.; James, D. E.; Ramm, G. Regulation of glucose transporter 4 translocation by the Rab guanosine triphosphate-activating protein AS160/TBC1D4: role of phosphorylation and membrane association. Mol. Endocrinol. 2008, 22, 2703-2715.
55. Inoki, K.; Zhu, T.; Guan, K.-L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003, 115, 577-590.
56. Bader, A. G.; Felts, K. A.; Jiang, N.; Chang, H. W.; Vogt, P. K. Y box-binding protein 1 induces resistance to oncogenic transformation by the phosphatidylinositol 3-kinase pathway. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 12384-12389.
57. Bader, A. G.; Vogt, P. K. Inhibition of protein synthesis by Y boxbinding protein 1 blocks oncogenic cell transformation. Mol. Cell. Biol. 2005, 25, 2095-2106.
58. Holcik, M.; Sonenberg, N. Translational control in stress and apoptosis. Nat. Rev. Mol. Cell. Biol. 2005, 6, 318-327.
59. Dever, T. E. Gene-specific regulation by general translation factors. Cell 2002, 108, 545-556.
60. Blais, J. D.; Addison, C. L.; Edge, R.; Falls, T.; Zhao, H.; Wary, K.; Koumenis, C.; Harding, H. P.; Ron, D.; Holcik, M.; Bell, J. C. PERK-dependent translational regulation promotes tumor cell adaptation and angiogenesis in response to hypoxic stress. Mol. Cell. Biol. 2006, 26, 9517-9532.
61. Mounir, Z.; Krishnamoorthy, J. L.; Wang, S.; Papadopoulou, B.; Campbell, S.; Muller, W. J.; Hatzoglou, M.; Koromilas, A. E. Akt determines cell fate through inhibition of the PERK-eIF2d phosphorylation pathway. S.T.K.E. 2011, 4, 192 ra62.
62. Majumder, P. K.; Febbo, P. G.; Bikoff, R.; Berger, R.; Xue, Q.; McMahon, L. M.; Manola, J.; Brugarolas, J.; McDonnell, T. J.; Golub, T. R.; Loda, M.; Lane, H. A.; Sellers, W. R. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat. Med. 2004, 10, 594-601.
63. Porstmann, T.; Santson, C. R.; Griffiths, B.; Cully, M.; Wu, M.; Leevers, S.; Griffiths, J. R.; Chung, Y.-L.; Schulze, A. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 2008, 8, 224-236.
64. Sundqvist, A.; Bengoechea-Alonso, M. T.; Ye, X.; Lukiyanchuk, V.; Jin, J.; Harper, J. W.; Ericsson, J. Control of lipid metabolism by phosphorylation-dependent degradation of the SREBP family of transcription factors by SCF(Fbw7). Cell Metab. 2005, 1, 379-391.
65. Yecies, J. L.; Manning, B. D. Transcriptional control of cellular metabolism by mTOR signaling. Cancer Res. 2011, 71, 2815-2820.
66. Lewis, C. A.; Griffiths, B.; Santos, C. R.; Pende, M.; Schulze, A. Regulation of the SREBP transcription factors by mTORC1. Biochem. Soc. Trans. 2011, 39, 495-499.
67. Peterson, T. R.; Sengupta, S. S.; Harris, T. E.; Carmack, A. E.; Kang, S. A.; Balderas, E.; Guertin, D. A.; Madden, K. L.; Carpenter, A. E.; Finck, B. N.; Sabatini, D. M. mTOR complex 1 regulates lipin localization to control the SREBP pathway. Cell 2011, 146, 408-420.
68. Guo, D.; Prins, R. M.; Dang, J.; Kuga, D.; Iwanami, A.; Soto, H.; Lin, K. Y.; Huang, T. T.; Akhavan, D.; Hock, M. B.; Zhu, S.; Kofman, A. A.; Bensinger, S. J.; Yong, W. H.; Vinters, H. V.; Horvath, S.; Watson, A. D.; Kuhn, J. G.; Robins, H. I.; Mehta, M. P.; Wen, P. Y.; DeAngelis, L. M.; Prados, M. D.; Mellinghoff, I. K.; Cloughesy, T. F.; Mischel, P. S. EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy. S.T.K.E. 2009, 2, 101 ra82.
69. Brunet, A.; Bonni, A.; Zigmond, M. J.; Lin, M. Z.; Juo, P.; Hu, L. S.; Anderson, M. J.; Arden, K. C.; Blenis, J.; Greenberg, M. E. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999, 96, 857-868.
70. Gan, B.; Lim, C.; Chu, G.; Hua, S.; Ding, Z.; Collins, M.; Hu, J.; Jiang, S.; Fletcher-Sananikone, E.; Zhuang, L.; Chang, M; Zheng, H,; Wang, Y. A.; Kwiatkowski, D. J.; Kaelin, W. G.; Signoretti, S.; DePinho, R. A. FoxOs enforce a progression checkpoint to constrain mTORC1-activated renal tumorigenesis. Cancer Cell 2010, 18, 472-484.
71. Greer, E. L.; Brunet, A. FOXO transcription factors at the interplay between longevity and tumor suppression. Oncogene 2005, 24, 7410-7425.
72. Romashkova, J. A.; Makarov, S. NF-κB is a target of AKT in antiapoptotic PDGF signaling. Nature 1999, 401, 86-90.
73. Madrid, L. V.; Mayo, M. W.; Reuther, J. Y.; Baldwin, A. S. Akt stimulates the transactivation potential of the RelA/p65 subunit of NF-κB through utilization of the IκB kinase and activation of the mitogen-activated protein kinase p38. J. Biol. Chem. 2001, 276, 18934-18940.
74. Beraud, C.; Henzel, W. J.; Baeuerle, P. A. Involvement of regulatory and catalytic subunits of phosphoinositide 3-kinase in NF-κB activation. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 429-434.
75. Asano, T.; Yao, Y.; Zhu, J.; Li, D.; Abbruzzese, J. L.; Reddy, S. A. The PI3-kinase/Akt signaling pathway is activated due to aberrant PTEN expression and targets transcription factors NF-κB and c-Myc in pancreatic cancer. Oncogene 2004, 23, 8571-8580.
76. Ali, A.; Hoeflich, K. P.; Woodgett, J. R. Glycogen synthase kinase-3: Properties, functions, and regulation. Chem. Rev. 2001, 101, 2527-2540.
77. Grinkevich, W.; Nikulenkov, F.; Shi, Y.; Enge, M.; Bao, W.; Maljukova, A.; Gluch, A.; Kel, A.; Sangfelt, O.; Selivanova, G. Ablation of key oncogenic pathways by RITA-activated p53 is required for efficient apoptosis. Cancer Cell 2009, 15, 441-453.
78. Inoki, K.; Ouyang, H.; Zhu, T.; Lindvall, C.; Wang, Y.; Zhang, X.; Yang, Q.; Bennett, C.; Harada, Y.; Stankunas, K.; Wang, C. Y.; He, X.; MacDougald, O. A.; You, M.; Williams, B. O.; Guan, K. L. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 2006, 126, 955-968.
79. Missy, K.; Van Poucke, V.; Raynal, P.; Viala, C.; Mauco, G.; Plantavid, M.; Chap, H.; Payrastre, B. Lipid products of phosphoinositide 3-kinase interact with Rac1 GTPase and stimulate GDP dissociation. J. Biol. Chem. 1998, 273, 30279-30286.
80. Zhang, F.; Zhang, X.; Li, M.; Chen, P.; Zhang, B.; Guo, H.; Cao, W.; Wei, X.; Cao, X.; Hao, X.; Zhang, N. mTOR complex component rector interacts with PKCccand regulates cancer cell metastasis. Cancer Res. 2010, 70, 9360-9370.
81. Scharenberg, A. M.; El-Hillal, O.; Fruman, D. A.; Beitz, L. O.; Li, Z.; Lin, S.; Gout, I.; Cantley, L. C.; Rawlings, D. J.; Kinet, J. P. EMBO 1998, 17, 1961-1972.
82. Ashcroft, M.; Ludwig, R. L.; Woods, D. B.; Copeland, T. D.; Weber, H. O.; MacRae, E. J.; Vousden, K. H. Phosphorylation of HDM2 by Akt. Oncogene 2002, 21, 1955-1962.
83. Du, K.; Montminy, M. CREB is a regulatory target for the protein kinase Akt/PKB. J. Biol. Chem. 1998, 273, 32377-32379.
84. Diehl, J. A.; Cheng, M.; Rouseel, M. F.; Sherr, C. J. Glycogen synthase kinase-3ssregulates cyclin D proteolysis and subcellular localization. Genes Dev. 1998, 12, 3499-4511.
85. Delpuech, O.; Griffiths, B.; East, P.; Essafi, A.; Lam, E. W.-F.; Burgering, B.; Downward, J.; Schulze, A. Induction of Mxi1-SRB by FOXO3a contributes to repression of myc-dependent gene expression. Mol. Cell. Biol. 2007, 27, 4917-4930.
86. Schild, C.; Wirth, M.; Reichert, M.; Schmid, R. M.; Saur, D.; Schneider, G. PI3K signaling maintains c-myc expression to regulate transcription of E2F1 in pancreatic cancer cells. Mol. Carcinog. 2009, 48, 1149-1158.
87. Nakayama, K. I.; Nakayama, K. Ubiquitin ligases: cell cycle control and cancer. Nat. Rev. Cancer 2006, 6, 369-381.
88. Reichert, M.; Saur, D.; Hamacher, R.; Schmid, R. M.; Schneider, G. Phosphoinositide 3-kinase signaling controls S-phase kinaseassociated protein 2 via E2F1 in pancreatic ductal adenocarcinoma cells. Cancer Res. 2007, 67, 4149-4156.
89. Lin, H.-K.; Wang, G.; Chen, Z.; Teruya-Feldstein, J.; Liu, Y.; Chan, C. H.; Yang, W. L.; Erdjument-Bromage, H.; Nakayama, K. I.; Nimer, S.; Tempst, P.; Pandolfi, P. P. Phosphorylationdependent regulation of cytosolic localization and oncogenic function of Skp2 by Akt/PKB. Nat. Cell. Biol. 2009, 11, 420-432.
90. Kim, J.; Jonasch, E.; Alexander, A.; Short, J. D.; Cai, S.; Wen, S.; Tsavachidou, D.; Tamboli, P.; Czerniak, B. A.; Do, K. A.; Wu, K. J.; Marlow, L. A.; Wood, C. G.; Copland, J. A.; Walker, C. L. Cytoplasmic sequestration of p27 via Akt phosphorylation in renal cell carcinoma. Clin. Cancer Res. 2009, 15, 81-89.
91. Pegg, A. E. Regulation of ornithine decarboxylase. J. Biol. Chem. 2006, 281, 14529-14532.
92. Falcon, B. L.; Barr, S.; Gokhale, P. C.; Chou, J.; Fogarty, J.; Depeille, P.; Miglarese, M.; Epstein, D. M.; McDonald, D. M. Reduced VEGF production, angiogenesis, and vascular regrowth contribute to the antitumor properties of dual mTORC1/mTORC2 inhibitors. Cancer Res. 2011, 71, 1573-1583.
93. Schnell, C. R.; Stauffer, F.; Allegrini, P. R.; O'Reilly, T.; McSheehy. P. M.; Dartois, C.; Stumm, M.; Cozens, R.; Littlewood-Evans, A.; Garcia-Echeverria, C.; Maira, S. M. Effects of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 on the tumor vasculature: Implications for clinical imaging. Cancer Res. 2008, 68, 6598-6607.
94. Phung, T. L.; Ziv, K.; Dabydeen, D.; Eyiah-Mensah, G.; Riveros, M.; Perruzzi, C.; Sun, J.; Monahan-Earley, R. A.; Shiojima, I.; Nagy, J. A.; Lin, M. I.; Walsh, K.; Dvorak, A. M.; Briscoe, D. M.; Neeman, M.; Sessa, W. C.; Dvorak, H. F.; Benjamin, L. E. Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin. Cancer Cell 2006, 10, 159-170.
95. De Benedetti, A.; Graff, J. R. eIF4E expression and its role in malignancies and metastases. Oncogene 2004, 23, 3189-3199.
96. Kaelin, W. The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer. Nat. Rev. Cancer. 2008, 8, 865-873.
97. Hudson, C. C.; Liu, M.; Chiang, G. G.; Otterness, D. M.; Loomis, D. C.; Kaper, F.; Giaccia, A. J.; Abraham, R. T. Regulation of hypoxia-inducible factor 1hhexpression and function by the mammalian target of rapamycin. Mol. Cell. Biol. 2002, 22, 7004-7014.
98. Toschi, A.; Lee, E.; Gadir, N.; Ohh, M.; Foster, D. A. Differential dependence of HIF1ddand HIF2aaon mTORC1 and mTORC2. J. Biol. Chem. 2008, 283, 34495-34499.
99. Land, S. C.; Tee, A. R. Hypoxia-inducible factor 1[is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif. J. Biol. Chem. 2007, 282, 20534-20543.
100. Sourbier, C.; Lindner, V.; Lang, H.; Agouni, A.; Schordan, E.; Danilin, S.; Rothhut, S.; Jaqmin, D.; Helwig, J.-J.; Massfelder, T. The phosphoinositide 3-kinase/Akt pathway: A new target in human renal cell carcinoma therapy. Cancer Res. 2006, 66, 5130-5142.
101. O'Reilly, K. E.; Rojo, F.; She, Q.-B.; Solit, D.; Mills, G. B.; Smith, D.; Lane, H.; Hofmann, F.; Hicklin, D. J.; Ludwig, D. L.; Baselga, J.; Rosen, N. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006, 66, 1500-1508.
102. Chandarlapaty, S.; Sawai, A.; Scaltriti, M.; Rodrik-Outmezguine, V.; Grbovic-Huezo, O.; Serra, V.; Majumder, P. K.; Baselga, J.; Rosen, N. Akt inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 2011, 19, 58-71.
103. Rodrik-Outmezguine, V.; Chandarlapaty, S.; Pagano, N. C.; Poulikakos, P. I.; Scaltriti, M.; Moskatel, E.; Baselga, J.; Guichard, S.; Rosen, N. mTOR kinase inhibition causes feedback-dependent biphasic regulation of Akt signaling. Cancer Disc. 2011, 1, 248-259.
104. Alessi, D. R.; Pearce, L. R.; Garcia-Martinez, J. M. New insights into mTOR signaling: mTORC2 and beyond. S.T.K.E. 2009, 2, 67 pe27.
105. Loewith, R.; Jacinto, E.; Wullschleger, S.; Lorberg, A.; Crespo, J. L.; Bonenfant, D.; Oppliger, W.; Jenoe, P.; Hall, M. N. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell 2002, 10, 457-468.
106. Julien, L. A.; Carriere, A.; Moreau, J.; Roux, P. P. mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling. Mol. Cell. Biol. 2010, 30, 908-921.
107. Dibble, C. C.; Asara, J. M.; Manning, B. D. Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1. Mol. Cell. Biol. 2009, 29, 5657-5670.
108. Hsu, P. P.; Kang, S. A.; Rameseder, J.; Zhang, Y.; Ottina, K. A.; Lim, D.; Peterson, T. R.; Choi, Y.; Gray, N. S.; Yaffe, M. B.; Marto, J. A.; Sabatini, D. M. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 2011, 332, 1317-1322.
109. Yu, Y.; Yoon, S.-O.; Poulogiannis, G.; Yang, Q.; Ma, X. M.; Villen, J.; Kubica, N.; Hoffman, G. R.; Cantley, L. C.; Gygi, S. P.; Blenis, J. Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science 2011, 332, 1322-1326.
110. Zhou, X. M.; Liu, Y.; Payne, G.; Lutz, R. J.; Chittenden, T. Growth factors inactivate the cell death promoter BAD by phosphorylation of its BH3 domain on Ser155. J. Biol. Chem. 2000, 275, 25046-25051.
111. Choo, A. Y.; Yoon, S.-O.; Kim, S. G.; Roux, P. P.; Blenis, J. Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 17414-17419.
112. Choo, A. Y.; Blenis, J. Not all substrates are treated equally: implications for mTOR, rapamycin-resistance and cancer therapy. Cell Cycle 2009, 8, 567-572.
113. Sun, S.-Y.; Rosenberg, L. M.; Wang, X.; Zhou, Z.; Yeu, P.; Fu, H.; Khuri, F. R. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res. 2005, 65, 7052-7058.
114. Wander, S. A.; Hennesey, B. T.; Slingerland, J. M. Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy. J. Clin. Invest. 2011, 121, 12231-41.
115. Guertin, D. A.; Sabatini, D. M. The pharmacology of mTOR inhibition. S.T.K.E. 2009, 2, 67 pe24.
116. Janes, M. R.; Limon, J. J.; So, L.; Chen, J.; Lim, R. J.; Chavez, M. A.; Vu, C.; Lilly, M. B.; Mallya, S.; Ong, S. T.; Konopleva, M.; Martin, M. B.; Ren, P.; Liu, Y.; Rommel, C.; Fruman, D. A. Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nat. Med. 2010, 16, 205-213.
117. Yu, K.; Shi, C.; Toral-Barza, L.; Lucas, J.; Shor, B.; Kim, J. E.; Zhang, W. G.; Mahoney, R.; Gaydos, C.; Tardio, L.; Kim, S. K.; Conant, R.; Curran, K.; Kaplan, J.; Verheijen, J.; Ayral-Kaloustian, S.; Mansour, T. S.; Abraham, R. T.; Zask, A.; Gibbons, J. J. Beyond rapalog therapy: Preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2. Cancer Res. 2010, 70, 621-631.
118. Carretero, J.; Shimamura, T.; Rikova, K.; Jackson, A. L.; Wilkerson, M. D.; Borgman, C. L.; Buttarazzi, M. S.; Sanofsky, B. A.; McNamara, K. L.; Brandstetter, K. A.; Walton, Z. E.; Gu, T. L.; Silva, J. C.; Crosby, K.; Shapiro, G. I.; Maira, S. M.; Ji, H.; Castrillon, D. H.; Kim, C. F.; Garcia-Echeverria, C.; Bardessy, N.; Sharpless, N E.; Hayes, N. D.; Kim, W. Y.; Engelman, J. A.; Wong, K. K. Integrative genomic and proteomic analyses identify targets for Lkb1-deficient metastatic lung tumors. Cancer Cell 2010, 17, 547-559.
119. Zheng, B.; Jeong, J. H.; Asara, J. M.; Yuan, Y. Y.; Granter, S. R.; Chin, L.; Cantley, L. C. Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation. Mol. Cell 2009, 33, 237-247.
120. Parry, L.; Maynard, J. H.; Patel, A.; Clifford, S. C.; Morrisey, C.; Maher, E. R.; Cheadle, J. P.; Sampson, J. R. Analysis of the TSC1 and TSC2 genes in sporadic renal cell carcinomas. Br. J. Cancer 2001, 85, 1226-1230.
121. Kucejova, B.; Pena-Llopis, S.; Yamasaki, T.; Sivanand, S.; Tran, T. A.; Alexander, S.; Wolff, N. C.; Lotan, Y.; Xie, X. J.; Kabbani, W.; Kapur, P.; Brugarolas, J. Interplay between pVHL and mTORC1 pathways in clear-cell renal cell carcinoma. Mol. Cancer Res. 2011, 9, 1255-1265.
122. Kuo, H.-P.; Lee, D.-F.; Chen, C.-T.; Liu, M.; Chou, C.-K.; Lee, H. J.; Du, Y.; XIe, X.; Wei, Y.; Xia, W.; Weihua, Z.; Yang, J. Y.; Yen, C. J.; Huang, T. H.; Tan, M.; Xing, G.; Zhao, Y.; Lin, C. H.; Tsai, S. F.; Fidler, I, J.; Hung, M. C. ARD1 stabilization of TSC2 suppresses tumorigenesis through the mTOR signaling pathway. S.T.K.E. 2010, 3, 108 ra9.
123. Fan, Q.-W.; Cheng, C.; Knight, Z. A.; Haas-Kogan, D.; Stokoe, D.; James, C. D.; McCormick, F.; Shokat, K. M.; Weiss, W. A. EGFR signals to mTOR through PKC and independently of Akt in glioma. S.T.K.E. 2009, 2, 55 ra4.
124. Whittaker, S.; Martin, M.; Marais, R. All roads lead to the ribosome. Cancer Cell 2010, 18, 5-6.
125. She, Q.-B.; Halilovic. E.; Ye, Q.; Zhen, W.; Shirasawa, S.; Sasazuki, T.; Solit, D. B.; Rosen, N. 4E-BP1 is a key effector of the oncogenic activation of the Akt and ERK signaling pathways that integrate their functions in tumors. Cancer Cell 2010, 18, 39-51.
126. Di Nicolantonio, F.; Arena, S.; Tabernero, J.; Grosso, S.; Molinari, F.; Macarulla, T.; Russo, M.; Cancelliere, C.; Zecchin, D.; Mazzacchelli, L.; Sasazuki, T.; Shirasawa, S.; Geuna, M.; Frattini, M.; Baselga, J.; Gallicchio, M.; Biffo, S.; Bardelli, A. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J. Clin. Invest. 2010, 120, 2858-2866.
127. Lee, D. F.; Kuo, H. P.; Chen, C. T.; Hsu, J. M.; Chou, C. K.; Wei, Y.; Sun, H. L.; Li, L. Y.; Ping, B.; Huang, W. C.; He, X.; Hung, J. Y.; Lai, C. C.; Ding, Q.; Su, J. L.; Yang, J. Y.; Sahin, A. A.; Hortobagyi, G. N.; Tsai, F. J.; Tsai, C. H.; Hung, M. C. IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell 2007, 130, 440-455.
128. Yang, H.; Minamishima, Y. A.; Yan, Q.; Schlisio, S.; Ebert, B. L.; Zhang, X.; Zhang, L.; Kim, W. Y.; Olumi, A. F.; Kaelin, W. G. pVHL acts as an adaptor to promote the inhibitory phosphoryation of the NF-kappaB agonist Card9 by CK2. Mol. Cell 2007, 28, 15-27.
129. Gurova, K. V.; Hill, J. E.; Guo, C.; Prokvolit, A.; Burdelya, L. G.; Samoylova, E.; Khodyakova, A. V.; Ganapathi, R.; Ganapathi, M.; Tararova, N. D.; Bosykh, D.; Lvovskiy, D.; Webb, T. R.; Stark, J. R.; Gudkov, A. V. Small molecules that reactivate p53 in renal cell carcinoma reveal a NF-κB-dependent mechanism of p53 suppression in tumors. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 17448-17453.
130. Lu, Z. H.; Shvartsman, M. B.; Lee, A. Y.; Shao, J. M.; Murray, M. M.; Kladney, R. D.; Fan, D.; Krajewski, S.; Chiang, G. G.; Mills, G. B.; Arbeit, J. M. Mammalian target of rapamycin activator RHEB is frequently overexpressed in human carcinomas and is critical and sufficient for skin epithelial carcinogenesis. Cancer Res. 2010, 70, 3287-3298.
131. Torbett, N. E.; Luna-Moran, A.; Knight, Z. A.; Houk, A.; Moasser, M.; Weiss, W.; Shokat, K. M.; Stokoe, D. A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI3K isoform-selective inhibition. Biochem. J. 2008, 415, 97-110.
132. Workman, P.; Clarke, P. A.; Raynaud, F. I.; van Montfort, R. L. M. Drugging the PI3 kinome: From chemical tools to drugs in the clinic. Cancer Res. 2010, 70, 2146-2157.
133. Edgar, K. A.; Wallin, J. J.; Berry, M.; Lee, L. B.; Prior, W. W.; Sampath, D.; Friedman, L. S.; Belvin, M. Isoform-specific phosphoinositide 3-kinase inhibitors exert distinct effects in solid tumors. Cancer Res. 2010, 70, 1164-1172.
134. Guerreiro, A. S.; Fattet, S.; Fischer, B.; Shalaby, T.; Jackson, S. P.; Schoenwaelder, S. M.; Grotzer, M. A.; Delattre, O.; Arcaro, A. Targeting the PI3K p110alpha isoform inhibits medulloblastoma proliferation, chemoresistance, and migration. Clin. Cancer Res. 2008, 14, 6761-6769.
135. Wee, S.; Wiederschain, D.; Maira, S. M.; Loo, A.; Miller, C.; deBeaumont, R.; Stegmeier, F.; Yao, Y. M.; Lengauer, C. PTENdeficient cancers depend on PIK3CB. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 13057-13062.
136. Fruman, D. A.; Rommel, C. PI3K[inhibitors in cancer: rationale and serendipity merge in the clinic. Cancer Discov. 2011, 1, 562-572.
137. McMillin, D. W.; Ooi, M.; Delmore, J.; Negri, J.; Hayden, P.; Mitsiades, N.; Jakubikova, J.; Maira, S. M.; Garcia-Echeverria, C.; Schlossman, R.; Munshi, N. C.; Richardson, P. G.; Anderson, K. C.; Misiades, C. S. Antimyeloma activity of the orally bioavailable dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235. Cancer Res. 2009, 69, 5835-5842.
138. Serra, V.; Markman, B.; Scalriti, M.; Eichhorn, P. J.; Valero, V.; Guzman, M.; Botero, M. L.; Llonch, E.; Atzori, F.; DiCosimo, S.; Maira, M.; Garcia-Echeverria, C.; Parra, J. L.; Arribas, J.; Baselga, J. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 2008, 68, 8022-8030.
139. Dan, S.; Okamura, M.; Seki, M.; Yamazaki, K.; Sugita, H.; Okui, M.; Mukai, Y.; Nishimura, H.; Asaka, R.; Nomura, K.; Ishikawa, Y.; Yamori, T. Correlating phosphatidylinositol 3-kinase inhibitor efficacy with signaling pathway status: In silico and biological evaluations. Cancer Res. 2010, 70, 4982-4994.
140. Ihle, N. T.; Lemos, R.; Wipf, P.; Yacoub, A.; Mitchell, C.; Siwak, D.; Mills, G. B.; Dent, P.; Kirkpatrick, D. L.; Powis, G. Mutations in the phosphatidylinositol 3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance. Cancer Res. 2009, 69, 143-150.
141. Ilic, N.; Utermark, T.; Widlund, H. R.; Roberts, T. M. PI3Ktargeted therapy can be evaded by gene amplification along the MYC-eukaryotic translation initiator factor 4E (eIF4E) axis. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, E699-E708.
142. Gera, J. F.; Mellinghoff, I. K.; Shi, Y.; Rettig, M. B.; Tran, C.; Hsu, J. H.; Sawyers, C. L.; Lichtenstein, A. K. Akt activity determines sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating cyclin D1 and c-myc expression. J. Biol. Chem. 2004, 279, 2737-2746.