Cancer therapy targeting the HER2-PI3K pathway: Potential impact on the heart

Frontiers in Pharmacology

Volumn 3 JUN, Issue , 2012, Pages

  Klement, Giannoula L ^a,b   Goukassian, David ^a   Hlatky, Lynn ^a   Carrozza, Joseph ^a   Morgan, James P ^a   Yan, Xinhua ^a  

^a TUFTS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b TUFTS MEDICAL CENTER   (United States)

Author keywords

Akt; Cancer; Cardiotoxicity; HER2; mTOR; PI3K

Indexed keywords

1 (1 CYANO 1 METHYLETHYL) 3 METHYL 8 (3 QUINOLINYL)IMIDAZO[4,5 C]QUINOLIN 2(1H,3H) ONE; 4 (4 AMINO 5 (7 METHOXY 1H INDOL 2 YL)IMIDAZO[5,1 F][1,2,4]TRIAZIN 7 YL)CYCLOHEXANECARBOXYLIC ACID; 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; 8 [4 (1 AMINOCYCLOBUTYL)PHENYL] 9 PHENYL 1,2,4 TRIAZOLO[3,4 F][1,6]NAPHTHYRIDIN 3(2H) ONE; ANTINEOPLASTIC AGENT; AZD 5363; AZD 8055; BGT 226; BUPARLISIB; BYL 719; CETUXIMAB; ERLOTINIB; EVEROLIMUS; GDC 0032; GDC 0068; GDC 0980; GEFITINIB; GSK 1059615; IDELALISIB; INK 1117; LAPATINIB; PERIFOSINE; PF 4691502; PICTILISIB; PKI 587; RAPAMYCIN; TEMSIROLIMUS; TRASTUZUMAB; UNCLASSIFIED DRUG; UNINDEXED DRUG; VANDETANIB; XL 147; XL 418;

ANTINEOPLASTIC ACTIVITY; ARTICLE; BREAST CANCER; CANCER CHEMOTHERAPY; CELL DIFFERENTIATION; CELL GROWTH; CELL METABOLISM; CELL PROLIFERATION; CELL SURVIVAL; DRUG POTENCY; DRUG TARGETING; ENZYME ACTIVITY; HEART DISEASE; HEART FUNCTION; HEART STRESS; HEMATOLOGIC MALIGNANCY; HER2 PI3K SIGNALING PATHWAY; LUNG CANCER; MOLECULAR DOCKING; NONHUMAN; OVARY CANCER; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; PROTEIN TARGETING; SEQUENCE HOMOLOGY; SIGNAL TRANSDUCTION; SQUAMOUS CELL CARCINOMA; TRANSGENIC MOUSE;

EID: 84866166653     PISSN: None     EISSN: 16639812     Source Type: Journal    
DOI: 10.3389/fphar.2012.00113     Document Type: Article

References (88)

1. Aoyagi, T., and Matsui, T. (2011). Phosphoinositide-3 kinase signaling in cardiac hypertrophy and heart failure. Curr. Pharm. Des. 17, 1818-1824.
2. Beretta, L., Gingras, A. C., Svitkin, Y. V., Hall, M. N., and Sonenberg, N. (1996). Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits capdependent initiation of translation. EMBO J. 15, 658-664.
3. Boluyt, M. O., Li, Z. B., Loyd, A. M., Scalia, A. F., Cirrincione, G. M., and Jackson, R. R. (2004). The mTOR/p70S6K signal transduction pathway plays a role in cardiac hypertrophy and influences expression of myosin heavy chain genes in vivo. Cardiovasc. Drugs Ther. 18, 257-267.
4. Brazil, D. P., Yang, Z. Z., and Hemmings, B. A. (2004). Advances in protein kinase B signalling: AKTion on multiple fronts. Trends Biochem. Sci. 29, 233-242.
5. Bruning, J. C., Michael, M. D., Winnay, J. N., Hayashi, T., Horsch, D., Accili, D., Goodyear, L. J., and Kahn, C. R. (1998). A musclespecific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol. Cell 2, 559-569.
6. Cantley, L. C. (2002). The phosphoinositide 3-kinase pathway. Science 296, 1655-1657.
7. Ceci, M., Ross, J. Jr., and Condorelli, G. (2004). Molecular determinants of the physiological adaptation to stress in the cardiomyocyte: a focus on AKT. J. Mol. Cell. Cardiol. 37, 905-912.
8. Chaanine,A.H.,andHajjar,R. J. (2011). AKT signalling in the failing heart. Eur. J. Heart Fail. 13, 825-829.
9. Chang, Z., Zhang, Q., Feng, Q., Xu, J., Teng, T., Luan, Q., Shan, C., Hu, Y., Hemmings, B. A., Gao, X., and Yang, Z. (2010). Deletion of Akt1 causes heart defects and abnormal cardiomyocyte proliferation. Dev. Biol. 347, 384-391.
10. Cho, H., Thorvaldsen, J. L., Chu, Q., Feng, F., and Birnbaum, M. J. (2001). Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J. Biol. Chem. 276, 38349-38352.
11. Citri, A., Skaria, K. B., and Yarden, Y. (2003). The deaf and the dumb: the biology of ErbB-2 and ErbB-3. Exp. Cell Res. 284, 54-65.
12. Citri, A., and Yarden, Y. (2006). EGF-ERBB signalling: towards the systems level. Nat. Rev. Mol. Cell Biol. 7,505-516.
13. Condorelli, G., Drusco, A., Stassi, G., Bellacosa, A., Roncarati, R., Iaccarino, G., Russo, M. A., Gu, Y., Dalton, N., Chung, C., Latronico, M. V., Napoli, C., Sadoshima, J., Croce, C. M., and Ross, J. Jr. (2002). Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice. Proc. Natl. Acad. Sci. U.S.A. 99, 12333-12338.
14. Crackower, M. A., Oudit, G. Y., Kozieradzki, I., Sarao, R., Sun, H., Sasaki, T., Hirsch, E., Suzuki, A., Shioi, T., Irie-Sasaki, J., Sah, R., Cheng, H. Y., Rybin, V. O., Lembo, G., Fratta, L., Oliveira-Dos-Santos, A. J., Benovic, J. L., Kahn, C. R., Izumo, S., Steinberg, S. F., Wymann, M. P., Backx, P. H., and Penninger, J. M. (2002). Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell 110, 737-749.
15. Crone, S. A., Zhao, Y Y, Fan, L., Gu, Y., Minamisawa, S., Liu, Y., Peterson, K. L., Chen, J., Kahn, R., Condorelli, G., Ross,J.Jr.,Chien,K.R.,andLee,K.F. (2002). ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat. Med. 8, 459-465.
16. DeBosch, B., Sambandam, N., Weinheimer, C., Courtois, M., and Muslin, A. J. (2006a). Akt2 regulates cardiac metabolism and cardiomyocyte survival. J. Biol. Chem. 281, 32841-32851.
17. DeBosch, B., Treskov, I., Lupu, T. S., Weinheimer, C., Kovacs, A., Courtois, M., and Muslin, A. J. (2006b). Akt1 is required for physiological cardiac growth. Circulation 113, 2097-2104.
18. Di,R.,Wu,X.,Chang,Z., Zhao, X., Feng, Q., Lu, S., Luan, Q., Hemmings, B. A., Li, X., and Yang, Z. (2012). S6K inhibition renders cardiac protection against myocardial infarction through PDK1 phosphorylation of Akt. Biochem. J. 441, 199-207.
19. Di, R. M., Feng, Q. T., Chang, Z., Luan, Q., Zhang, Y Y., Huang, J., Li, X. L., and Yang, Z. Z. (2010). PDK1 plays a critical role in regulating cardiac function in mice and human. Chin. Med. J. 123, 2358-2363.
20. Dickerson, E. B., Blackburn, W. H., Smith, M. H., Kapa, L. B., Lyon, L. A., and Mcdonald, J. F. (2010). Chemosensitization of cancer cells by siRNA using targeted nanogel delivery. BMC Cancer 10, 10. doi:10.1186/1471-2407-10-10
21. Dorn, G. W. II, and Force, T. (2005). Protein kinase cascades in the regulation of cardiac hypertrophy.J. Clin. Invest. 115,527-537.
22. Dummler, B., and Hemmings, B. A. (2007). Physiological roles of PKB/Akt isoforms in development and disease. Biochem. Soc. Trans. 35, 231-235.
23. Etzion, S., Etzion, Y., Debosch, B., Crawford, P. A., and Muslin, A. J. (2010). Akt2 deficiency promotes cardiac induction of Rab4a and myocardial betaadrenergic hypersensitivity. J. Mol. Cell. Cardiol. 49, 931-940.
24. Francia, G., Shaked, Y., Hashimoto, K., Sun, J., Yin, M., Cesta, C.,Xu, P., Man, S., Hackl, C., Stewart, J., Uhlik, M., Dantzig, A. H., Foster, S., and Kerbel, R. S. (2012). Lowdose metronomic oral dosing of a prodrug of Gemcitabine (LY2334737) causes antitumor effects in the absence of inhibition of systemic vasculogenesis. Mol. Cancer Ther. 11,680-689.
25. Fruman, D. A., Meyers, R. E., and Cantley, L. C. (1998). Phosphoinositide kinases. Annu. Rev. Biochem. 67, 481-507.
26. Gaidarov, I., and Keen, J. H. (1999). Phosphoinositide-AP-2 interactions required for targeting to plasma membrane clathrincoated pits. J. Cell Biol. 146, 755-764.
27. Gao, X. M., Wong, G., Wang, B., Kiriazis, H., Moore, X. L., Su, Y D., Dart, A., and Du, X. J. (2006). Inhibition of mTOR reduces chronic pressureoverload cardiac hypertrophy and fibrosis. J. Hypertens. 24, 1663-1670.
28. Garcia-Echeverria, C., and Sellers, W R. (2008). Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene 27, 5511-5526.
29. Ghigo, A., Morello, F., Perino, A., Damilano, F., and Hirsch, E. (2011). Specific PI3K isoform modulation in heart failure: lessons from transgenic mice. Curr. Heart Fail Rep. 8, 168-175.
30. Guy, P. M., Platko, J. V., Cantley, L. C., Cerione, R. A., and Carraway, K. L. III. (1994). Insect cellexpressed p180erbB3 possesses an impaired tyrosine kinase activity. Proc. Natl. Acad. Sci. U.S.A. 91, 8132-8136.
31. Hait, W. N., and Hambley, T. W. (2009). Targeted cancer therapeutics. Cancer Res. 69, 1263-1267; discussion 1267.
32. Haubner, B. J., Neely G. G., Voelkl, J. G., Damilano, F., Kuba, K., Imai, Y., Komnenovic,V.,Mayr,A., Pachinger, O., Hirsch, E., Penninger, J. M., and Metzler, B. (2010). PI3Kgamma protects from myocardial ischemia and reperfusion injury through a kinaseindependent pathway. PLoS ONE 5, e9350. doi:10.1371/journal.pone.0009350
33. Hers, I., Vincent, E. E., and Tavare, J. M. (2011). Akt signalling in health and disease. Cell. Signal. 23, 1515-1527.
34. Heineke, J., and Molkentin, J. D. (2006). Regulation of cardiac hypertrophy by intracellular signaling pathways. Nat. Rev. Mol. Cell Biol. 7, 589-600.
35. Hershman, D. L., and Shao, T. (2009). Anthracycline cardiotoxicity after breast cancer treatment. Oncology 23, 227-234.
36. Hirsch, E., Katanaev, V. L., Garlanda, C., Azzolino, O., Pirola, L., Silengo, L., Sozzani, S., Mantovani, A., Altruda, F., and Wymann, M. P. (2000). Central role for G proteincoupled phosphoinositide 3-kinase gamma in inflammation. Science 287, 1049-1053.
37. Ito, K., Akazawa, H., Tamagawa, M., Furukawa, K., Ogawa, W., Yasuda, N., Kudo, Y., Liao, C. H., Yamamoto, R., Sato, T., Molkentin, J. D., Kasuga, M., Noda, T., Nakaya, H., and Komuro, I. (2009). PDK1 coordinates survival pathways and betaadrenergic response in the heart. Proc. Natl. Acad. Sci. U.S.A. 106, 8689-8694.
38. Klapper, L. N., Glathe, S., Vaisman, N., Hynes, N. E., Andrews, G. C., Sela, M., and Yarden, Y (1999). The ErbB-2/HER2 oncoprotein of human carcinomas may function solely as a shared coreceptor for multiple stromaderived growth factors. Proc. Natl. Acad. Sci. U.S.A. 96, 4995-5000.
39. Klein, P. M., and Dybdal, N. (2003). Trastuzumab and cardiac dysfunction: update on preclinical studies. Semin. Oncol. 305 (5 Suppl. 16), 49-53.
40. Klement, G., Baruchel, S., Rak, J., Man, S., Clark, K., Hicklin, D. J., Bohlen, P., and Kerbel, R. S. (2000). Continuous lowdose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J. Clin. Invest. 105,R15-R24.
41. Lawlor, M. A., and Alessi, D. R. (2001). PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? J. Cell. Sci. 114, 2903-2910.
42. Lee, K. F., Simon, H., Chen, H., Bates, B., Hung, M. C., and Hauser, C. (1995). Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 378, 394-398.
43. Li, X., Mikhalkova, D., Gao, E., Zhang, J., Myers, V.,Zincarelli, C., Lei, Y., Song, J., Koch, W. J., Peppel, K., Cheung, J. Y., Feldman, A. M., and Chan, T. O. (2011). Myocardial injury after ischemiareperfusion in mice deficient in Akt2 is associated with increased cardiac macrophage density. Am. J. Physiol Heart Circ. Physiol. 301,H1932-H1940.
44. Li, Z., Jiang, H., Xie, W., Zhang, Z., Smrcka, A. V., and Wu, D. (2000). Roles of PLC-beta2 and -beta3 and PI3Kgamma in chemoattractantmediated signal transduction. Science 287, 1046-1049.
45. Lin, R. C., Weeks, K. L., Gao, X. M., Williams, R. B., Bernardo, B. C., Kiriazis, H., Matthews, V. B., Woodcock, E. A., Bouwman, R. D., Mollica, J. P., Speirs, H. J., Dawes, I. W., Daly, R. J., Shioi, T., Izumo, S., Febbraio, M. A., Du,X.J.,andMcmullen,J.R. (2010). PI3K(p110 alpha) protects against myocardial infarctioninduced heart failure: identification of PI3K-regulated miRNA and mRNA. Arterioscler. Thromb. Vasc. Biol. 30, 724-732.
46. Liu, P., Cheng, H., Roberts, T. M., and Zhao, J. J. (2009). Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. Drug Discov. 8, 627-644.
47. Luo, J., Manning, B. D., and Cantley, L. C. (2003). Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 4, 257-262.
48. Luo, J., Mcmullen, J. R., Sobkiw, C. L., Zhang, L., Dorfman, A. L., Sherwood, M. C., Logsdon, M. N., Horner, J. W., Depinho, R. A., Izumo, S., and Cantley, L. C. (2005). Class IA phosphoinositide 3-kinase regulates heart size and physiological cardiac hypertrophy. Mol. Cell. Biol. 25, 9491-9502.
49. Matsui, T., Li, L., Wu, J. C., Cook, S. A., Nagoshi, T., Picard, M. H., Liao, R., and Rosenzweig, A. (2002). Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart. J. Biol. Chem. 277, 22896-22901.
50. Matsui, T., and Rosenzweig, A. (2005). Convergent signal transduction pathways controlling cardiomyocyte survival and function: the role of PI 3-kinase and Akt. J. Mol. Cell. Cardiol. 38, 63-71.
51. McMullen, J. R., Amirahmadi, F., Woodcock, E. A., Schinke-Braun, M., Bouwman, R. D., Hewitt, K. A., Mollica, J. P., Zhang, L., Zhang, Y., Shioi, T., Buerger, A., Izumo, S., Jay, P. Y., and Jen nings, G. L. (2007). Protective effects of exercise and phospho inositide 3-kinase(p110alpha) signaling in dilated and hypertrophic cardiomyopathy. Proc. Natl. Acad. Sci. U.S.A. 104, 612-617.
52. McMullen, J. R., Sherwood, M. C., Tarnavski, O., Zhang, L., Dorfman, A. L., Shioi, T., and Izumo, S. (2004). Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload. Circulation 109, 3050-3055.
53. McMullen, J. R., Shioi, T., Zhang, L., Tarnavski, O., Sherwood, M. C., Kang, P. M., and Izumo, S. (2003). Phosphoinositide 3-kinase(p110alpha) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy. Proc. Natl. Acad. Sci. U.S.A. 100, 12355-12360.
54. Mora, A., Davies, A. M., Bertrand, L., Sharif, I., Budas, G. R., Jovanovic, S., Mouton, V., Kahn, C. R., Lucocq, J. M., Gray, G. A., Jovanovic, A., and Alessi, D. R. (2003). Deficiency of PDK1 in cardiac muscle results in heart failure and increased sensitivity to hypoxia. EMBO J. 22, 4666-4676.
55. Morisco, C., Condorelli, G., Trimarco, V., Bellis, A., Marrone, C., Sadoshima, J., and Trimarco, B. (2005). Akt mediates the crosstalk between betaadrenergic and insulin receptors in neonatal cardiomyocytes. Circ. Res. 96, 180-188.
56. Morris, J. K., Lin, W., Hauser, C., Marchuk, Y., Getman, D., and Lee, K. E (1999). Rescue of the cardiac defect in ErbB2 mutant mice reveals essential roles of ErbB2 in peripheral nervous system development. Neuron 23, 273-283.
57. Muslin, A. J. (2011). Akt2: a critical regulator of cardiomyocyte survival and metabolism. Pediatr. Cardiol. 32, 317-322.
58. NagaPrasad, S. V., Laporte, S. A., Chamberlain, D., Caron, M. G., Barak, L., and Rockman, H. A. (2002). Phosphoinositide 3-kinase regulates beta2-adrenergic receptor endocytosis by AP-2 recruitment to the receptor/beta-arrestin complex. J. Cell Biol. 158,563-575.
59. Nienaber, J. J., Tachibana, H., Naga Prasad, S. V., Esposito, G., Wu, D., Mao, L., and Rockman, H. A. (2003). Inhibition of receptorlocalized PI3K preserves cardiac beta-adrenergic receptor function and ameliorates pressure overload heart failure. J. Clin. Invest. 112, 1067-1079.
60. Oudit, G. Y., Crackower, M. A., Eriksson, U., Sarao, R., Kozieradzki, I., Sasaki, T., Irie-Sasaki, J., Gidrewicz, D., Rybin, V. O., Wada, T., Steinberg, S. F., Backx, P. H., and Penninger, J. M. (2003). Phosphoinositide 3-kinase gammadeficient mice are protected from isoproterenolinduced heart failure. Circulation 108,2147-2152.
61. Oudit, G. Y., and Penninger, J. M. (2009). Cardiac regulation by phosphoinositide 3-kinases and PTEN. Cardiovasc. Res. 82, 250-260.
62. Ozcelik, C., Erdmann, B., Pilz, B., Wettschureck, N., Britsch, S., Hubner, N., Chien, K. R., Birchmeier, C., and Garratt, A. N. (2002). Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy. Proc. Natl. Acad. Sci. U.S.A. 99, 8880-8885.
63. Patrucco, E., Notte, A., Barberis, L., Selvetella, G.,Maffei,A.,Brancaccio,M., Marengo, S., Russo, G., Azzolino, O., Rybalkin, S. D., Silengo, L., Altruda, E, Wetzker, R., Wymann, M. P., Lembo, G., and Hirsch, E. (2004). PI3Kgamma modulates the cardiac response to chronic pressure overload by distinct kinasedependent and -independent effects. Cell 118, 375-387.
64. Pretorius, L., Du, X. J., Woodcock, E. A., Kiriazis, H., Lin, R. C., Marasco, S., Medcalf, R. L., Ming, Z., Head, G. A., Tan, J. W., Cemerlang, N., Sadoshima, J., Shioi, T., Izumo, S., Lukoshkova, E. V., Dart, A. M., Jennings, G. L., and Mcmullen, J. R. (2009). Reduced phosphoinositide 3-kinase (p110alpha) activation increases the susceptibility to atrial fibrillation. Am. J. Pathol. 175, 998-1009.
65. Rota, M., Boni, A., Urbanek, K., Padin-Iruegas, M. E., Kajstura, T. J., Fiore, G., Kubo, H., Sonnenblick, E. H., Musso, E., Houser, S. R., Leri, A., Sussman, M. A., and Anversa, P. (2005). Nuclear targeting of Akt enhances ventricular function and myocyte contractility. Circ. Res. 97, 1332-1341.
66. Sarbassov, D. D., Guertin, D. A., Ali, S. M., and Sabatini, D. M. (2005). Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307,1098-1101.
67. Shaw, R. J., and Cantley, L. C. (2006). Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 441,424-430.
68. Shen, W H., Chen, Z., Shi, S., Chen, H., Zhu, W., Penner, A., Bu, G., Li, W., Boyle, D. W., Rubart, M., Field, L. J., Abraham, R., Liechty, E. A., and Shou, W (2008). Cardiac restricted overexpression of kinasedead mammalian target of rapamycin (mTOR) mutant impairs the mTOR-mediated signaling and cardiac function. J. Biol. Chem. 283, 13842-13849.
69. Shende, P., Plaisance, I., Morandi, C., Pellieux, C., Berthonneche, C., Zorzato, F., Krishnan, J., Lerch, R., Hall, M. N., Ruegg, M. A., Pedrazzini, T., and Brink, M. (2011). Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice. Circulation 123, 1073-1082.
70. Shioi, T., Kang, P. M., Douglas, P. S., Hampe, J., Yballe, C. M., Lawitts, J., Cantley, L. C., and Izumo, S. (2000). The conserved phosphoinositide 3-kinase pathway determines heart size in mice. EMBOJ. 19, 2537-2548.
71. Shioi, T., Mcmullen, J. R., Kang, P. M., Douglas, P. S., Obata, T., Franke, T. F., Cantley, L. C., and Izumo, S. (2002). Akt/protein kinase B promotes organ growth in transgenic mice. Mol. Cell. Biol. 22, 2799-2809.
72. Shioi, T., Mcmullen, J. R., Tarnavski, O., Converso, K., Sherwood, M. C., Manning, W. J., and Izumo, S. (2003). Rapamycin attenuates loadinduced cardiac hypertrophy in mice. Circulation 107,1664-1670.
73. Shiraishi, I., Melendez, J., Ahn, Y., Skavdahl, M., Murphy, E., Welch, S., Schaefer, E., Walsh, K., Rosenzweig, A., Torella, D., Nurzynska, D., Kajstura, J., Leri, A., Anversa, P., and Sussman, M. A. (2004). Nuclear targeting of Akt enhances kinase activity and survival of cardiomyocytes. Circ. Res. 94, 884-891.
74. Slamon, D. J., Leyland-Jones, B., Shak, S., Fuchs, H., Paton, V., Bajamonde, A., Fleming, T., Eiermann, W., Wolter, J., Pegram, M., Baselga, J., and Norton, L. (2001). Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl.J. Med. 344,783-792.
75. Soesanto, W., Lin, H. Y., Hu, E., Lefler, S., Litwin, S. E., Sena, S., Abel, E. D., Symons, J. D., and Jalili, T. (2009). Mammalian target of rapamycin is a critical regulator of cardiac hypertrophy in spontaneously hypertensive rats. Hypertension 54, 1321-1327.
76. Stephens, L. R., Eguinoa, A., Erdjument-Bromage, H., Lui, M., Cooke, F., Coadwell, J., Smrcka, A. S., Thelen, M., Cadwallader, K., Tempst, P., and Hawkins, P. T. (1997). The G beta gamma sensitivity of a PI3K is dependent upon a tightly associated adaptor, p101. Cell 89, 105-114.
77. Stoyanov, B., Volinia, S., Hanck, T., Rubio, I., Loubtchenkov, M., Malek, D., Stoyanova, S., Vanhaesebroeck, B., Dhand, R., Nurnberg, B., Gierschik, P., Seedorf, K., Hsuan, J. J., Waterfield, M. D., and Wetzker, R. (1995). Cloning and characterization of a G proteinactivated human phosphoinositide-3 kinase. Science 269, 690-693.
78. Tian, R. (2005). Another role for the celebrity: Akt and insulin resistance. Circ. Res. 96, 139-140.
79. Ueno, N. T., Bartholomeusz, C., Herrmann, J. L., Estrov, Z., Shao, R., Andreeff, M., Price, J., Paul, R. W., Anklesaria, P., Yu, D., and Hung, M. C. (2000). E1A-mediated paclitaxel sensitization in HER-2/neuoverexpressing ovarian cancer SKOV3.ip1 through apoptosis involving the caspase-3 pathway. Clin. Cancer Res. 6, 250-259.
80. Um, S. H., Frigerio, F., Watanabe, M., Picard, F., Joaquin, M., Sticker, M., Fumagalli, S., Allegrini, P. R., Kozma, S. C., Auwerx, J., and Thomas, G. (2004). Absence of S6K1 protects against age- and dietinduced obesity while enhancing insulin sensitivity. Nature 431, 200-205.
81. Yang, Z. Z., Tschopp, O., Hemmings-Mieszczak,M.,Feng,J.,Brodbeck,D., Perentes, E., and Hemmings, B. A. (2003). Protein kinase B alpha/Akt1 regulates placental development and fetal growth. J. Biol. Chem. 278, 32124-32131.
82. Yap, T. A., Garrett, M. D., Walton, M. I., Raynaud, F., De Bono, J. S., and Workman, P. (2008). Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises. Curr. Opin. Pharmacol. 8, 393-412.
83. Yarden, Y., and Sliwkowski, M. X. (2001). Untangling the ErbB signalling network. Nat. Rev. Mol. Cell Biol. 2, 127-137.
84. Yuan, T. L., and Cantley, L. C. (2008). PI3K pathway alterations in cancer: variations on a theme. Oncogene 27, 5497-5510.
85. Zhang, D., Contu, R., Latronico, M. V., Zhang, J., Rizzi, R., Catalucci, D., Miyamoto, S., Huang, K., Ceci, M., Gu, Y., Dalton, N. D., Peterson, K. L., Guan, K. L., Brown, J. H., Chen, J., Sonenberg, N., and Condorelli, G. (2010). MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice. J. Clin. Invest. 120,2805-2816.
86. Zhao, L., and Vogt, P. K. (2008). Class I PI3K in oncogenic cellular transformation. Oncogene 27, 5486-5496.
87. Zhu, W., Soonpaa, M. H., Chen, H., Shen, W., Payne, R. M., Liechty, E. A., Caldwell, R. L., Shou, W., and Field, L. J. (2009). Acute doxorubicin cardiotoxicity is associated with p53-induced inhibition of the mammalian target of rapamycin pathway. Circulation 119, 99-106.
88. Zoncu, R., Efeyan, A., and Sabatini, D. M. (2011). mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol. 12, 21-35.