The PIK3CA gene as a mutated target for cancer therapy

Current Cancer Drug Targets

Volumn 8, Issue 8, 2008, Pages 733-740

  Gustin, John P ^a,b   Cosgrove, David P ^a   Ben, Ho Park ^a,b  

^a JOHNS HOPKINS UNIVERSITY   (United States)

^b Johns Hopkins University   (United States)

Author keywords

AKT; mTOR; Mutation; Oncogene; PI3 kinase; PIK3CA

Indexed keywords

2 MORPHOLINO 8 PHENYLCHROMONE; API 2; BEZ 235; ERLOTINIB; GDC 0941; GEFITINIB; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MILTEFOSINE; PERIFOSINE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PROTEIN KINASE B BETA; PROTEIN KINASE B INHIBITOR; RAPAMYCIN; TEMSIROLIMUS; UNCLASSIFIED DRUG; WORTMANNIN; XL 147;

ANTINEOPLASTIC ACTIVITY; BREAST CANCER; CANCER INHIBITION; CANCER RESEARCH; DRUG RESEARCH; GENE; HUMAN; MALIGNANT NEOPLASTIC DISEASE; NONHUMAN; ONCOGENE; PIK3CA GENE; REVIEW; SOMATIC MUTATION; UNSPECIFIED SIDE EFFECT;

1-PHOSPHATIDYLINOSITOL 3-KINASE; ENZYME INHIBITORS; HUMANS; MUTATION; NEOPLASMS; PROTEIN KINASES; PROTO-ONCOGENE PROTEINS C-AKT;

EID: 57449083437     PISSN: 15680096     EISSN: None     Source Type: Journal    
DOI: 10.2174/156800908786733504     Document Type: Review

References (128)

1. O'Brien, S. G.; Guilhot, F.; Larson, R. A.; Gathmann, I.; Baccarani, M.; Cervantes, F.; Cornelissen, J. J.; Fischer, T.; Hochhaus, A.; Hughes, T.; Lechner, K.; Nielsen, J. L.; Rousselot, P.; Reiffers, J.; Saglio, G.; Shepherd, J.; Simonsson, B.; Gratwohl, A.; Goldman, J. M.; Kantarjian, H.; Taylor, K.; Verhoef, G.; Bolton, A. E.; Capdeville, R.; Druker, B. J.; Durrant, S.; Schwarer, A.; Joske, D.; Seymour, J.; Grigg, A.; Ma, D.; Arthur, C.; Bradstock, K.; Joshua, D.; Louwagie, A.; Martiat, P.; Straetmans, N.; Bosly, A.; Shustik, C.; Lipton, J.; Forrest, D.; Walker, I.; Roy, D. C.; Rubinger, M.; Bence-Bruckler, I.; Kovacs, M.; Turner, A. R.; Birgens, H.; Bjerrum, O.; Facon, T.; Harousseau, J. L.; Tulliez, M.; Guerci, A.; Blaise, D.; Maloisel, F.; Michallet, M.; Hossfeld, D.; Mertelsmann, R.; Andreesen, R.; Nerl, C.; Freund, M.; Gattermann, N.; Hoeffken, K.; Ehninger, G.; Deininger, M.; Ottmann, O.; Peschel, C.; Fruehauf, S.; Neubauer, A.; Le Coutre, P.; Aulitzky, W.; Fanin, R.; Rosti, G.; Mandelli, F.; Morra, E.; Carella, A.; Lazzarino, M.; Petrini, M.; Ferrini, P. R.; Nobile, F.; Liso, V.; Ferrara, F.; Rizzoli, V.; Fioritoni, G.; Martinelli, G.; Ossenkoppele, G.; Browett, P.; Gedde-Dahl, T.; Tangen, J. M.; Dahl, I.; Odriozola, J.; Boluda, J. C. H.; Steegmann, J. L.; Canizo, C.; Sureda, A.; Diaz, J.; Granena, A.; Fernandez, M. N.; Stenke, L.; Paul, C.; Bjoreman, M.; Malm, C.; Wadenvik, H.; Nilsson, P. G.; Turesson, I.; Hess, U.; Solenthaler, M.; Russel, N.; Mufti, G.; Cavenagh, J.; Clark, R. E.; Green, A. R.; Holyoake, T. L.; Lucas, G. S.; Smith, G.; Milligan, D. W.; Rule, S. J.; Burnett, A. K.; Moroose, R.; Wetzler, M.; Bearden, J.; Brown, R.; Lobell, M.; Cataland, S.; Rabinowitz, I.; Meisenberg, B.; Gabrilove, J.; Thompson, K.; Graziano, S.; Emanuel, P.; Gross, H.; Cobb, P.; Bhatia, R.; Dakhil, S.; Irwin, D.; Issell, B.; Pavletic, S.; Kuebler, P.; Layhe, E.; Butera, P.; Glass, J.; Moore, J.; Grant, B.; Niell, H.; Herzig, R.; Burris, H.; Peterson, B.; Powell, B.; Kalaycio, M.; Stirewalt, D.; Samlowski, W.; Berman, E.; Limentani, S.; Seay, T.; Shea, T.; Akard, L.; Becker, P.; DeVine, S.; Hart, R.; Veith, R.; Wade, J.; Brunvand, M.; Silver, R.; Kalman, L.; Strickland, D.; Shurafa, M.; Bashey, A.; Shadduck, R.; Cooper, S.; Safah, H.; Rubenstein, M.; Collins, R.; Keller, A.; Stone, R.; Tallman, M.; Stevens, D.; Pecora, A.; Agha, M.; Holmes, H.; Rowe, J.; Schiffer, C. A.; Buyse, M.; Cornelissen, J. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronicphase chronic myeloid leukemia. N. Engl. J. Med. 2003, 348, 994-1004.
2. Paez, J. G.; Janne, P. A.; Lee, J. C.; Tracy, S.; Greulich, H.; Gabriel, S.; Herman, P.; Kaye, F. J.; Lindeman, N.; Boggon, T. J.; Naoki, K.; Sasaki, H.; Fujii, Y.; Eck, M. J.; Sellers, W. R.; Johnson, B. E.; Meyerson, M. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004, 304, 1497-1500.
3. Lynch, T. J.; Bell, D. W.; Sordella, R.; Gurubhagavatula, S.; Okimoto, R. A.; Brannigan, B. W.; Harris, P. L.; Haserlat, S. M.; Supko, J. G.; Haluska, F. G.; Louis, D. N.; Christiani, D. C.; Settleman, J.; Haber, D. A. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 2004, 350, 2129-2139.
4. Romond, E. H.; Perez, E. A.; Bryant, J.; Suman, V. J.; Geyer, C. E.; Davidson, N. E.; Tan-Chiu, E.; Martino, S.; Paik, S.; Kaufman, P. A.; Swain, S. M.; Pisansky, T. M.; Fehrenbacher, L.; Kutteh, L. A.; Vogel, V. G.; Visscher, D. W.; Yothers, G.; Jenkins, R. B.; Brown, A. M.; Dakhil, S. R.; Mamounas, E. P.; Lingle, W. L.; Klein, P. M.; Ingle, J. N.; Wolmark, N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N. Engl. J. Med. 2005, 353, 1673-1684.
5. Piccart-Gebhart, M. J.; Procter, M.; Leyland-Jones, B.; Goldhirsch, A.; Untch, M.; Smith, I.; Gianni, L.; Baselga, J.; Bell, R.; Jackisch, C.; Cameron, D.; Dowsett, M.; Barrios, C. H.; Steger, G.; Huang, C. S.; Andersson, M.; Inbar, M.; Lichinitser, M.; Lang, I.; Nitz, U.; Iwata, H.; Thomssen, C.; Lohrisch, C.; Suter, T. M.; Ruschoff, J.; Suto, T.; Greatorex, V.; Ward, C.; Straehle, C.; McFadden, E.; Dolci, M. S.; Gelber, R. D. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N. Engl. J. Med. 2005, 353, 1659-1672.
6. Mass, R. D.; Press, M. F.; Anderson, S.; Cobleigh, M. A.; Vogel, C. L.; Dybdal, N.; Leiberman, G.; Slamon, D. J. Evaluation of clinical outcomes according to HER2 detection by fluorescence in situ hybridization in women with metastatic breast cancer treated with trastuzumab. Clin. Breast Cancer 2005, 6, 240-246.
7. Samuels, Y.; Wang, Z. H.; Bardelli, A.; Silliman, N.; Ptak, J.; Szabo, S.; Yan, H.; Gazdar, A.; Powell, D. 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 cancers. Science 2004, 304, 554-554.
8. Bachman, K. E.; Argani, P.; Samuels, Y.; Silliman, N.; Ptak, J.; Szabo, S.; Konishi, H.; Karakas, B.; Blair, B. G.; Lin, C.; Peters, B. A.; Velculescu, V. E.; Park, B. H. The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol. Ther. 2004, 3, 772-775.
9. Lee, J. W.; Soung, Y. H.; Kim, S. Y.; Lee, H. W.; Park, W. S.; Nam, S. W.; Kim, S. H.; Lee, J. Y.; Yoo, N. J.; Lee, S. H. PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. Oncogene, 2005, 24, 1477-1480.
10. Levine, D. A.; Bogomolniy, F.; Yee, C. J.; Lash, A.; Barakat, R. R.; Borgen, P. I.; Boyd, J. Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin. Cancer Res. 2005, 11, 2875-2878.
11. Campbell, I. G.; Russell, S. E.; Choong, D. Y. H.; Montgomery, K. G.; Ciavarella, M. L.; Hooi, C. S. F.; Cristiano, B. E.; Pearson, R. B.; Phillips, W. A. Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res. 2004, 64, 7678-7681.
12. Velho, S.; Oliveira, C.; Ferreira, A.; Ferreira, A. C.; Suriano, G.; Schwartz, S.; Duval, A.; Carneiro, F.; Machado, J. C.; Hamelin, R.; Seruca, R. The prevalence of PIK3CA mutations in gastric and colon cancer. Eur. J. Cancer 2005, 41, 1649-1654.
13. Li, V. S. W.; Wong, C. W.; Chan, T. L.; Chan, A. S. W.; Zhao, W.; Chu, K. M.; So, S.; Chen, X.; Yuen, S. T.; Leung, S. Y. Mutations of PIK3CA in gastric adenocarcinoma. BMC Cancer 2005, 5.
14. Kita, D.; Yonekawa, Y.; Weller, M.; Ohgaki, H. PIK3CA alterations in primary (de novo) and secondary glioblastomas. Acta Neuropathol. 2007, 113, 295-302.
15. Gallia, G. L.; Rand, V.; Siu, I. M.; Eberhart, C. G.; James, C. D.; Marie, S. K. N.; Oba-Shinjo, S. M.; Carlotti, C. G.; Caballero, O. L.; Simpson, A. J. G.; Brock, M. V.; Massion, P. P.; Carson, B. S.; Riggins, G. J. PIK3CA gene mutations in pediatric and adult glioblastoma multiforme. Mol. Cancer Res. 2006, 4, 709-714.
16. Dam, V.; Morgan, B. T.; Mazanek, P.; Hogarty, M. D. Mutations in PIK3CA are infrequent in neuroblastoma. BMC Cancer 2006, 6.
17. Pang, J. C. S.; Chung, N. Y. F.; Chan, N. H. L.; Poon, W. S.; Thomas, T.; Ng, H. K. Rare mutation of PIK3CA in meningiomas. Acta Neuropathol. 2006, 111, 284-285.
18. Hartmann, C.; Devermann, L.; Gehlhaar, C.; Holtkamp, N.; von Deimling, A. PIK3CA mutations in oligodendroglial tumours. Neuropathol. Appl. Neurobiol. 2006, 32, 209-212.
19. Hartmann, C.; Bartels, G.; Gehlhaar, C.; Holtkamp, N.; von Deimling, A. PIK3CA mutations in glioblastoma multiforme. Acta Neuropathol. 2005, 109, 639-642.
20. Mueller, W.; Mizoguchi, M.; Silen, E.; D'Amore, K.; Nutt, C. L.; Louis, D. N. Mutations of the PIK3CA gene are rare in human glioblastoma. Acta Neuropathol. 2005, 109, 654-655.
21. Broderick, D. K.; Di, C. H.; Parrett, T. J.; Samuels, Y. R.; Cummins, J. M.; McLendon, R. E.; Fults, D. W.; Velculescu, V. E.; Bigner, D. D.; Yan, H. Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas. Cancer Res. 2004, 64, 5048-5050.
22. Guo, X. N.; Rajput, A.; Rose, R.; Hauser, J.; Beko, A.; Kuropatwinski, K.; Levea, C.; Hoffman, R. M.; Brattain, N. G.; Wang, J. Mutant PIK3CA-bearing colon cancer cells display increased metastasis in an orthotopic model. Cancer Res. 2007, 67, 5851-5858.
23. Ikenoue, T.; Kanai, F.; Hikiba, Y.; Obata, T.; Tanaka, Y.; Imamura, J.; Ohta, M.; Jazag, A.; Guleng, B.; Tateishi, K.; Asaoka, Y.; Matsumura, M.; Kawabe, T.; Omata, M. Functional analysis of PIK3CA gene mutations in human colorectal cancer. Cancer Res. 2005, 65, 4562-4567.
24. Samuels, Y.; Diaz, L. A.; Schmidt-Kittler, O.; Cummins, J. M.; DeLong, L.; Cheong, I.; Rago, C.; Huso, D. L.; Lengauer, C.; Kinzler, K. W.; Vogelstein, B.; Velculescu, V. E. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 2005, 7, 561-573.
25. Isakoff, S. J.; Engelman, J. A.; Irie, H. Y.; Luo, J.; Brachmann, S. M.; Pearline, R. V.; Cantley, L. C.; Brugge, J. S. Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res. 2005, 65, 10992-11000.
26. Zhao, J. J.; Liu, Z. N.; Wang, L.; Shin, E.; Loda, M. F.; Roberts, T. M. The oncogenic properties of mutant p110 alpha and p110 beta phosphatidylinositol 3-kinases in human mammary epithelial cells. Proc. Natl. Acad. Sci. USA 2005, 102, 18443-18448.
27. Kang, S. Y.; Bader, A. G.; Vogt, P. K. Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc. Natl. Acad. Sci. USA 2005, 102, 802-807.
28. Bader, A. G.; Kang, S. Y.; Vogt, P. K. Cancer-specific mutations in PIK3CA are oncogenic in vivo. Proc. Natl. Acad. Sci. USA 2006, 103, 1475-1479.
29. Miled, N.; Yan, Y.; Hon, W. C.; Perisic, O.; Zvelebil, M.; Inbar, Y.; Schneidman-Duhovny, D.; Wolfson, H. J.; Backer, J. M.; Williams, R. L. Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science 2007, 317, 239-242.
30. Kang, S.; Bader, A. G.; Zhao, L.; Vogt, P. K. Mutated PI 3-kinases - Cancer targets on a silver platter. Cell Cycle 2005, 4, 578-581.
31. Maruyama, N.; Miyoshi, Y.; Taguchi, T.; Tamaki, Y.; Monden, M.; Noguchi, S. Clinicopathologic analysis of breast cancers with PIK3CA mutations in Japanese women. Clin. Cancer Res. 2007, 13, 408-414.
32. Pérez-Tenorio, G.; Alkhori, L.; Olsson, B.; Waltersson, M. A.; Nordenskjöld, B.; Rutqvist, L. E.; Skoog, L.; Stål, O. PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer. Clin. Cancer Res. 2007, 13, 3577-3584.
33. Li, S. Y.; Rong, M. N.; Grieu, F.; Iacopetta, B. PIK3CA mutations in breast cancer are associated with poor outcome. Breast Cancer Res. Treat. 2006, 96, 91-95.
34. Kato, S.; Iida, S.; Higuchi, T.; Ishikawa, T.; Takagi, Y.; Yasuno, M.; Enomoto, M.; Uetake, H.; Sugihara, K. PIK3CA mutation is predictive of poor survival in patients with colorectal cancer. Intl. J. Cancer 2007, 121, 1771-1778.
35. Barbareschi, M.; Buttitta, F.; Felicioni, L.; Cotrupi, S.; Barassi, F.; Del Grammastro, M.; Ferro, A.; Dalla Palma, P.; Galligioni, E.; Marchetti, A. Different Prognostic Roles of Mutations in the Helical and Kinase Domains of the PIK3CA Gene in Breast Carcinomas. Clin. Cancer Res. 2007, 13, 6064-6069.
36. Davies, M.; Hennessy, B.; Mills, G. B. Point mutations of protein kinases ion and individualised cancer therapy. Expert Opin. Pharmacother. 2006, 7, 2243-2261.
37. Pao, W.; Miller, V.; Zakowski, M.; Doherty, J.; Politi, K.; Sarkaria, I.; Singh, B.; Heelan, R.; Rusch, V.; Fulton, L.; Mardis, E.; Kupfer, D.; Wilson, R.; Kris, M.; Varmus, H. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc. Natl. Acad. Sci. USA 2004, 101, 13306-13311.
38. Weinstein, I. B. Cancer: Addiction to oncogenes - The Achilles heal of cancer. Science 2002, 297, 63-64.
39. Huang, C. H.; Mandelker, D.; Schmidt-Kittler, O.; Samuels, Y.; Velculescu, V. E.; Kinzler, K. W.; Vogelstein, B.; Gabelli, S. B.; Amzel, L. M. The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science 2007, 318, 1744-8.
40. Schultz, R. M.; Merriman, R. L.; Andis, S. L.; Bonjouklian, R.; Grindey, G. B.; Rutherford, P. G.; Gallegos, A.; Massey, K.; Powis, G. In-Vitro and in-Vivo Antitumor-Activity of the Phosphatidylinositol-3-Kinase Inhibitor, Wortmannin. Anticancer Res. 1995, 15, 1135-1139.
41. Semba, S.; Itoh, N.; Ito, M.; Harada, M.; Yamakawa, M. The in vitro and in vivo effects of 2-(4-morpholinyl)-8-phenyl-chromone (LY294002), a specific inhibitor of phosphatidylinositol 3 ′-kinase, in human colon cancer cells. Clin. Cancer Res. 2002, 8, 1957-1963.
42. Hu, L. M.; Zaloudek, C.; Mills, G. B.; Gray, J.; Jaffe, R. B. In vivo and in vitro ovarian carcinoma growth inhibition by a phosphatidylinositol 3-kinase inhibitor (LY294002). Clin. Cancer Res. 2000, 6, 880-886.
43. Workman, P. Inhibiting the phosphoinositide 3-kinase pathway for cancer treatment. Biochem. Soc. Trans. 2004, 32, 393-396.
44. Gharbi, S. I.; Zvelebil, M. J.; Shuttleworth, S. J.; Hancox, T.; Saghir, N.; Timms, J. F.; Waterfield, M. D. Exploring the specificity of the PI3K family inhibitor LY294002. Biochem. J. 2007, 404, 15-21.
45. Sarkaria, J. N.; Tibbetts, R. S.; Busby, E. C.; Kennedy, A. P.; Hill, D. E.; Abraham, R. T. Inhibition of phosphoinositide 3-kinase related kinases by the radiosensitizing agent wortmannin. Cancer Res. 1998, 58, 4375-4382.
46. Banin, S.; Moyal, L.; Shieh, S. Y.; Taya, Y.; Anderson, C. W.; Chessa, L.; Smorodinsky, N. I.; Prives, C.; Reiss, Y.; Shiloh, Y.; Ziv, Y. Enhanced phosphorylation of p53 by ATN in response to DNA damage. Science 1998, 281, 1674-1677.
47. Brunn, G. J.; Williams, J.; Sabers, C.; Wiederrecht, G.; Lawrence, J. C.; Abraham, R. T. Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002. EMBO J. 1996, 15, 5256-5267.
48. Hartley, K. O.; Gell, D.; Smith, G. C. M.; Zhang, H.; Divecha, N.; Connelly, M. A.; Admon, A.; Leesmiller, S. P.; Anderson, C. W.; Jackson, S. P. DNA-Dependent Protein-Kinase Catalytic Subunit - a Relative of Phosphatidylinositol 3-Kinase and the Ataxia-Telangiectasia Gene-Product. Cell 1995, 82, 849-856.
49. Hayakawa, M.; Kawaguchi, K. I.; Kaizawa, H.; Tomonobu, K.; Ohishi, T.; Yamano, M.; Okada, M.; Ohta, M.; Tsukamoto, S.; Raynaud, F. I.; Parker, P.; Workman, P.; Waterfield, M. D. Synthesis and biological evaluation of sulfonylhydrazone-substituted imidazo 1,2-a pyridines as novel PI3 kinase p110 alpha inhibitors. Bioorg. Med. Chem. 2007, 15, 5837-5844.
50. Hayakawa, M.; Kaizawa, H.; Moritomo, H.; Koizumi, T.; Ohishi, T.; Yamano, M.; Okada, M.; Ohta, M.; Tsukamoto, S.; Raynaud, F. I.; Workman, P.; Waterfield, M. D.; Parker, P. Synthesis and biological evaluation of pyrido 3 ′,2′: 4,5 furo 3,2-d pyrimidine derivatives as novel PI3 kinase p110 alpha inhibitors. Bioorg. Med. Chem. Lett. 2007, 17, 2438-2442.
51. Hayakawa, M.; Kaizawa, H.; Kawaguchi, K.; Ishikawa, N.; Koizumi, T.; Ohishi, T.; Yamano, M.; Okada, M.; Ohta, M.; Tsukamoto, S.; Raynaud, F. I.; Waterfield, M. D.; Parker, P.; Workman, P. Synthesis and biological evaluation of imidazo 1,2-a pyridine derivatives as novel PI3 kinase p110 alpha inhibitors. Bioorg. Med. Chem. 2007, 15, 403-412.
52. Hayakawa, M.; Kaizawa, H.; Moritomo, H.; Koizumi, T.; Ohishi, T.; Okada, M.; Ohta, M.; Tsukamoto, S.; Parker, P.; Workman, P.; Waterfield, M. Synthesis and biological evaluation of 4-morpholino-2-phenylquinazolines and related derivatives as novel PI3 kinase p110 alpha inhibitors. Bioorg. Med. Chem. 2006, 14, 6847-6858.
53. Marion, F.; Williams, D. E.; Patrick, B. O.; Hollander, I.; Mallon, R.; Kim, S. C.; Roll, D. M.; Feldberg, L.; Van Soest, R.; Andersen, R. J. Liphagal, a selective inhibitor of PI3 kinase alpha isolated from the sponge Aka coralliphaga: Structure elucidation and biomimetic synthesis. Org. Lett. 2006, 8, 321-324.
54. Ihle, N. T.; Paine-Murrieta, G.; Berggren, M. I.; Baker, A.; Tate, W. R.; Wipf, P.; Abraham, R. T.; Kirkpatrick, D. L.; Powis, G. The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non-small cell lung cancer xenografts. Mol. Cancer Ther. 2005, 4, 1349-1357.
55. Knight, Z. A.; Gonzalez, B.; Feldman, M. E.; Zunder, E. R.; Goldenberg, D. D.; Williams, O.; Loewith, R.; Stokoe, D.; Balla, A.; Toth, B.; Balla, T.; Weiss, W. A.; Williams, R. L.; Shokat, K. M. A pharmacological map of the PI3-K family defines a role for p110 alpha in insulin signaling. Cell 2006, 125, 733-747.
56. Ihle, N. T.; Williams, R.; Chow, S.; Chew, W.; Berggren, M. I.; Paine-Murrieta, G.; Minion, D. J.; Halter, R. J.; Wipf, P.; Abraham, R.; Kirkpatrick, L.; Powis, G. Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling. Mol. Cancer Ther. 2004, 3, 763-772.
57. Engelman, J. A.; Luo, J.; Cantley, L. C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat. Rev. Genet. 2006, 7, 606-619.
58. McMullen, J. R.; Jay, P. Y. PI3K(p110 alpha) inhibitors as anticancer agents - Minding the heart. Cell Cycle 2007, 6, 910-913.
59. Altomare, D. A.; Testa, J. R. Perturbations of the AKT signaling pathway in human cancer. Oncogene 2005, 24, 7455-7464.
60. Staal, S. P. Molecular-Cloning of the Akt Oncogene and Its Human Homologs Akt1 and Akt2 - Amplification of Akt1 in a Primary Human Gastric Adenocarcinoma. Proc. Natl. Acad. Sci. USA 1987, 84, 5034-5037.
61. Lin, X. D.; Murray, J. M.; Rico, A. C.; Wang, M. X.; Chu, D. T.; Zhou, Y. S.; Del Rosario, M.; Kaufman, S.; Ma, S.; Fang, E.; Crawford, K.; Jefferson, A. B. Discovery of 2-pyrimidyl-5-amidothiophenes as potent inhibitors for AKT: Synthesis and SAR studies. Bioorg. Med. Chem. Lett. 2006, 16, 4163-4168.
62. Zhu, G. D.; Gong, J. C.; Claiborne, A.; Woods, K. W.; Gandhi, V. B.; Thomas, S.; Luo, Y.; Liu, X. S.; Shi, Y.; Guan, R.; Magnone, S. R.; Klinghofer, V.; Johnson, E. F.; Bouska, J.; Shoemaker, A.; Oleksijew, A.; Stoll, V. S.; De Jong, R.; Oltersdorf, T.; Li, Q.; Rosenberg, S. H.; Giranda, V. L. Isoquinoline-pyridine-based protein kinase B/Akt antagonists: SAR and in vivo antitumor activity. Bioorg. Med. Chem. Lett. 2006, 16, 3150-3155.
63. Hideshima, T.; Catley, L.; Yasui, H.; Ishitsuka, K.; Raje, N.; Mitsiades, C.; Podar, K.; Munshi, N. C.; Chauhan, D.; Richardson, P. G.; Anderson, K. C. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood 2006, 107, 4053-4062.
64. Mandal, M.; Younes, M.; Swan, E. A.; Jasser, S. A.; Doan, D.; Yigitbasi, O.; McMurphey, A.; Ludwick, J.; El-Naggar, A. K.; Bucana, C.; Mills, G. B.; Myers, J. N. The Akt inhibitor KP372-1 inhibits proliferation and induces apoptosis and anoikis in squamous cell carcinoma of the head and neck. Oral Oncol. 2006, 42, 430-439.
65. Zeng, Z. H.; Samudio, I. J.; Zhang, W. G.; Estrov, Z.; Pelicano, H.; Harris, D.; Frolova, O.; Hail, N.; Chen, W. J.; Kornblau, S. M.; Huang, P.; Lu, Y. L.; Mills, G. B.; Andreeff, M.; Konopleva, M. Simultaneous inhibition of PDK1/AKT and Fms-like tyrosine kinase 3 signaling by a small-molecule KP372-1 induces mitochondrial dysfunction and apoptosis in acute myelogenous leukemia. Cancer Res. 2006, 66, 3737-3746.
66. Koul, D.; Shen, R. J.; Bergh, S.; Sheng, X. Y.; Shishodia, S.; Lafortune, T. A.; Lu, Y. L.; de Groot, J. F.; Mills, G. B.; Yung, W. K. A. Inhibition of Akt survival pathway by a small-molecule inhibitor in human glioblastoma. Mol. Cancer Ther. 2006, 5, 637-644.
67. Gills, J. J.; Holbeck, S.; Hollingshead, M.; Hewitt, S. M.; Kozikowski, A. P.; Dennis, P. A. Spectrum of activity and molecular correlates of response to phosphatidylinositol ether lipid analogues, novel lipid-based inhibitors of Akt. Mol. Cancer Ther. 2006, 5, 713-722.
68. Li, Q.; Woods, K. W.; Thomas, S.; Zhu, G. D.; Packard, G.; Fisher, J.; Li, T. M.; Gong, J. C.; Dinges, J.; Song, X. H.; Abrams, J.; Luo, Y.; Johnson, E. F.; Shi, Y.; Liu, X. S.; Klinghofer, V.; Jong, R. D.; Oltersdorf, T.; Stoll, V. S.; Jakob, C. G.; Rosenberg, S. H.; Giranda, V. L. Synthesis and structure-activity relationship of 3,4 ′-bispyridinylethylenes: Discovery of a potent 3-isoquinolinylpyridine inhibitor of protein kinase B (PKB/Akt) for the treatment of cancer. Bioorg. Med. Chem. Lett. 2006, 16, 2000-2007.
69. Li, Q.; Li, T. M.; Zhu, G. D.; Gong, J. C.; Claibone, A.; Dalton, C.; Luo, Y.; Johnson, E. F.; Shi, Y.; Liu, X. S.; Klinghofer, V.; Bauch, J. L.; Marsh, K. C.; Bouska, J. J.; Arries, S.; De Jong, R.; Oltersdorf, T.; Stoll, V. S.; Jakob, C. G.; Rosenberg, S. H.; Giranda, V. L. Discovery of trans-3,4 ′-bispyridinylethylenes as potent and novel inhibitors of protein kinase B (PKB/Akt) for the treatment of cancer: Synthesis and biological evaluation. Bioorg. Med. Chem. Lett. 2006, 16, 1679-1685.
70. Tang, H. J.; Jin, X. H.; Wang, S. M.; Yang, D. J.; Cao, Y. Y.; Chen, J. Y.; Gossett, D. R.; Lin, J. Y. A small molecule compound inhibits AKT pathway in ovarian cancer cell lines. Gynecol. Oncol. 2006, 100, 308-317.
71. Georgakis, G. V.; Li, Y.; Rassidakis, G. Z.; Medeiros, L. J.; Mills, G. B.; Younes, A. Inhibition of the phosphatidylinositol-3 kinase/Akt promotes G1 cell cycle arrest and apoptosis in Hodgkin lymphoma. Br. J. Haematol. 2006, 132, 503-511.
72. Shi, Y.; Liu, X. S.; Han, E. K.; Guan, R.; Shoemaker, A. R.; Oleksijew, A.; Woods, K. W.; Fisher, J. P.; Klinghofer, V.; Lasko, L.; McGonigal, T.; Li, Q.; Rosenberg, S. H.; Giranda, V. L.; Luo, Y. Optimal classes of chemotherapeutic agents sensitized by specific small-molecule inhibitors of Akt in vitro and in vivo. Neoplasia 2005, 7, 992-1000.
73. Luo, Y.; Shoemaker, A. R.; Liu, X. S.; Woods, K. W.; Thomas, S. A.; de Jong, R.; Han, E. K.; Li, T. M.; Stoll, V. S.; Powlas, J. A.; Oleksijew, A.; Mitten, M. J.; Shi, Y.; Guan, R.; McGonigal, T. P.; Klinghofer, V.; Johnson, E. F.; Leverson, J. D.; Bouska, J. J.; Mamo, M.; Smith, R. A.; Gramling-Evans, E. E.; Zinker, B. A.; Mika, A. K.; Nguyen, P. T.; Oltersdorf, T.; Rosenberg, S. H.; Li, Q.; Giranda, V. L. Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo. Mol. Cancer Ther. 2005, 4, 77-986.
74. Mandal, M.; Kim, S.; Younes, M. N.; Jasser, S. A.; El-Naggar, A. K.; Mills, G. B.; Myers, J. N. The Akt inhibitor KP372-1 suppresses Akt activity and cell proliferation and induces apoptosis in thyroid cancer cells. Br. J. Cancer 2005, 92, 1899-1905.
75. Shin, I.; Edl, J.; Biswas, S.; Lin, P. C.; Mernaugh, R.; Arteaga, C. L. Proapoptotic activity of cell-permeable anti-Akt single-chain antibodies. Cancer Res. 2005, 65, 2815-2824.
76. Lindsley, C. W.; Zhao, Z. J.; Leister, W. H.; Robinson, R. G.; Barnett, S. F.; Defeo-Jones, D.; Jones, R. E.; Hartman, G. D.; Huff, J. R.; Huber, H. E.; Duggan, M. E. Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors. Bioorg. Med. Chem. Lett. 2005, 15, 761-764.
77. Barnett, S. F.; Defeo-Jones, D.; Fu, S.; Hancock, P. J.; Haskell, K. M.; Jones, R. E.; Kahana, J. A.; Kral, A. M.; Leander, K.; Lee, L. L.; Malinowski, J.; McAvoy, E. M.; Nahas, D. D.; Robinson, R. G.; Huber, H. E. Identification and characterization of pleckstrin-omology-domain-dependent and isoenzyme-specific Akt inhibitors. Biochem. J. 2005, 385, 399-408.
78. Hiromura, M.; Okada, F.; Obata, T.; Auguin, D.; Shibata, T.; Roumestand, C.; Noguchi, M. Inhibition of Akt kinase activity by a peptide spanning the beta A strand of the proto-oncogene TCL1. J. Biol. Chem. 2004, 279, 53407-53418.
79. Meuillet, E. J.; Ihle, N.; Baker, A. F.; Gard, J. M.; Stamper, C.; Williams, R.; Coon, A.; Mahadevan, D.; George, B. L.; Kirkpatrick, L.; Powis, G. In vivo molecular pharmacology and antitumor activity of the targeted Akt inhibitor PX-316. Oncol. Res. 2004, 14, 513-527.
80. Jin, X.; Gossett, D. R.; Wang, S.; Yang, D.; Cao, Y.; Chen, J.; Guo, R.; Reynolds, R. K.; Lin, J. Inhibition of AKT survival pathway by a small molecule inhibitor in human endometrial cancer cells. Br. J. Cancer 2004, 91, 1808-1812.
81. Shaw, Y. J.; Yang, Y. T.; Garrison, J. B.; Kyprianou, N.; Chen, C. S. Pharmacological exploitation of the alpha 1-adrenoreceptor antagonist doxazosin to develop a novel class of antitumor agents that block intracellular protein kinase B/Akt activation. J. Med. Chem. 2004, 47, 4453-4462.
82. Yang, L.; Dan, H. C.; Sun, M.; Liu, Q. Y.; Sun, X. M.; Feldman, R. I.; Hamilton, A. D.; Polokoff, M.; Nicosia, S. V.; Herlyn, M.; Sebti, S. M.; Cheng, J. Q. Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt. Cancer Res. 2004, 64, 4394-4399.
83. Castillo, S. S.; Brognard, J.; Petukhov, P. A.; Zhang, C. Y.; Tsurutani, J.; Granville, C. A.; Li, M.; Jung, M.; West, K. A.; Gills, J. G.; Kozikowski, A. P.; Dennis, P. A. Preferential inhibition of Akt and killing of Akt-dependent cancer cells by rationally designed phosphatidylinositol ether lipid analogues. Cancer Res. 2004, 64, 2782-2792.
84. Luo, Y.; Smith, R. A.; Guan, R.; Liu, X. S.; Klinghofer, V.; Shen, J. W.; Hutchins, C.; Richardson, P.; Holzman, T.; Rosenberg, S. H.; Giranda, V. L. Pseudosubstrate peptides inhibit Akt and induce cell growth inhibition. Biochemistry 2004, 43, 1254-1263.
85. Kondapaka, S. B.; Singh, S. S.; Dasmahapatra, G. P.; Sausville, E. A.; Roy, K. K. Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation. Mol. Cancer Ther. 2003, 2, 1093-1103.
86. Meuillet, E. J.; Mahadevan, D.; Vankayalapati, H.; Berggren, M.; Williams, R.; Coon, A.; Kozikowski, A. P.; Powis, G. Specific inhibition of the Akt1 pleckstrin homology domain by D-3-deoxyphosphatidyl-myo-inositol analogues. Mol. Cancer Ther. 2003, 2, 389-399.
87. Ruiter, G. A.; Zerp, S. F.; Bartelink, H.; van Blitterswijk, W. J.; Verheij, M. Anti-cancer alkyl-lysophospholipids inhibit the phosphatidylinositol 3-kinase-Akt/PKB survival pathway. Anti-Cancer Drugs 2003, 14, 167-173.
88. Reuveni, H.; Livnah, N.; Geiger, T.; Kleid, S.; Ohne, O.; Cohen, I.; Benhar, M.; Gellerman, G.; Levitzki, A. Toward a PKB inhibitor: Modification of a selective PKA inhibitor by rational design. Biochemistry 2002, 41, 10304-10314.
89. Vink, S. R.; Lagerwerf, S.; Mesman, E.; Schellens, J. H. M.; Begg, A. C.; van Blitterswijk, W. J.; Verheij, M. Radiosensitization of squamous cell carcinoma by the alkylphospholipid perifosine in cell culture and xenografts. Clin. Cancer Res. 2006, 12, 1615-1622.
90. Li, X.; Luwor, R.; Lu, Y.; Liang, K.; Fan, Z. Enhancement of antitumor activity of the anti-EGF receptor monoclonal antibody cetuximab/C225 by perifosine in PTEN-deficient cancer cells. Oncogene 2006, 25, 525-535.
91. Rahmani, M.; Reese, E.; Dai, Y.; Bauer, C.; Payne, S. G.; Dent, P.; Spiegel, S.; Grant, S. Coadministration of histone deacetylase inhibitors and perifosine synergistically induces apoptosis in human leukemia cells through Akt and ERK1/2 inactivation and the generation of ceramide and reactive oxygen species. Cancer Res. 2005, 65, 2422-2432.
92. Smorenburg, C. H.; Seynaeve, C.; Bontenbal, M.; Planting, A.; Sindermann, H.; Verweij, J. Phase II study of miltefosine 6% solution as topical treatment of skin metastases in breast cancer patients. Anti-Cancer Drugs 2000, 11, 825-828.
93. Clive, S.; Gardiner, J.; Leonard, R. C. F. Miltefosine as a topical treatment for cutaneous metastases in breast carcinoma. Cancer Chemother. Pharmacol. 1999, 44, S29-S30.
94. Terwogt, J. M. M.; Mandjes, I. A. M.; Sindermann, H.; Beijnen, J. H.; Huinink, W. Phase II trial of topically applied miltefosine solution in patients with skin-metastasized breast cancer. Br. J. Cancer 1999, 79, 1158-1161.
95. Dummer, R.; Krasovec, M.; Roger, J.; Sindermann, H.; Burg, G. Topical Administration of Hexadecylphosphocholine in Patients with Cutaneous Lymphomas - Results of a Phase-I/Ii Study. J. Am. Acad. Dermatol. 1993, 29, 963-970.
96. Feun, L. G.; Blessing, J. A.; Barrett, R. J.; Hanjani, P. A Phase-Ii Trial of Tricyclic Nucleoside Phosphate in Patients with Advanced Squamous-Cell Carcinoma of the Cervix - a Gynecologic-Oncology-Group Study. Am. J. Clin. Oncol.-Cancer Clin. Trials 1993, 16, 506-508.
97. Feun, L. G.; Savaraj, N.; Bodey, G. P.; Lu, K.; Yap, B. S.; Ajani, J. A.; Burgess, M. A.; Benjamin, R. S.; McKelvey, E.; Krakoff, I. Phase-1 Study of Tricyclic Nucleoside Phosphate Using a 5-Day Continuous Infusion Schedule. Cancer Res. 1984, 44, 3608-3612.
98. Yoeli-Lerner, M.; Yiu, G. K.; Rabinovitz, I.; Erhardt, P.; Jauliac, S.; Toker, A. Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT. Molecular Cell 2005, 20, 539-550.
99. Chen, W. S.; Xu, P. Z.; Gottlob, K.; Chen, M. L.; Sokol, K.; Shiyanova, T.; Roninson, I.; Weng, W.; Suzuki, R.; Tobe, K.; Kadowaki, T.; Hay, N. Growth retardation and increased apoptosis in mice with homozygous disruption of the akt1 gene. Genes Dev. 2001, 15, 2203-2208.
100. Cho, H.; Mu, J.; Kim, J. K.; Thorvaldsen, J. L.; Chu, Q. W.; Crenshaw, E. B.; Kaestner, K. H.; Bartolomei, M. S.; Shulman, G. I.; Birnbaum, M. J. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 2001, 292, 1728-1731.
101. Tschopp, O.; Yang, Z. Z.; Brodbeck, D.; Dummler, B. A.; Hemmings-Mieszczak, M.; Watanabe, T.; Michaelis, T.; Frahm, J.; Hemmings, B. A. Essential role of protein kinase B gamma (PKB gamma/Akt3) in postnatal brain development but not in glucose homeostasis. Development 2005, 132, 2943-2954.
102. Wullschleger, S.; Loewith, R.; Hall, M. N. TOR signaling in growth and metabolism. Cell 2006, 124, 471-484.
103. Bernardi, R.; Guernah, I.; Jin, D.; Grisendi, S.; Alimonti, A.; Teruya-Feldstein, J.; Cordon-Cardo, C.; Simon, M. C.; Rafii, S.; Pandolfi, P. P. PML inhibits HIF-1 alpha translation and neoangiogenesis through repression of mTOR. Nature 2006, 442, 779-785.
104. Sehgal, S. N.; Baker, H.; Vezina, C. Rapamycin (Ay-22,989), a New Antifungal Antibiotic. II. Fermentation, Isolation and Characterization. J. Antibiot. 1975, 28, 727-732.
105. Neuhaus, P.; Klupp, J.; Langrehr, J. M. mTOR inhibitors: An overview. Liver Transplant. 2001, 7, 473-484.
106. Franz, D. N.; Leonard, J.; Tudor, C.; Chuck, G.; Care, M.; Sethuraman, G.; Dinopoulos, A.; Thomas, G.; Crone, K. R. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann. Neurol. 2006, 59, 490-498.
107. Galanis, E.; Buckner, J. C.; Maurer, M. J.; Kreisberg, J. L.; Ballman, K.; Boni, J.; Peralba, J. M.; Jenkins, R. B.; Dakhil, S. R.; Morton, R. F.; Jaeckle, K. A.; Scheithauer, B. W.; Dancey, J.; Hidalgo, M.; Walsh, D. J. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: A north central cancer treatment group study. J. Clin. Oncol. 2005, 23, 5294-5304.
108. Chan, S.; Scheulen, M. E.; Johnston, S.; Mross, K.; Cardoso, F.; Dittrich, C.; Eiermann, W.; Hess, D.; Morant, R.; Semiglazov, V.; Borner, M.; Salzberg, M.; Ostapenko, V.; Illiger, H. J.; Behringer, D.; Bardy-Bouxin, N.; Boni, J.; Kong, S.; Cincotta, M.; Moore, L. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J. Clin. Oncol. 2005, 23, 5314-5322.
109. Witzig, T. E.; Geyer, S. M.; Ghobrial, I.; Inwards, D. J.; Fonseca, R.; Kurtin, P.; Ansell, S. M.; Luyun, R.; Flynn, P. J.; Morton, R. F.; Dakhil, S. R.; Gross, H.; Kaufmann, S. H. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J. Clin. Oncol. 2005, 23, 5347-5356.
110. Margolin, K.; Longmate, J.; Baratta, T.; Synold, T.; Christensen, S.; Weber, J.; Gajewski, T.; Quirt, I.; Doroshow, J. H. CCI-779 in metastatic melanoma - A phase II trial of the California Cancer Consortium. Cancer 2005, 104, 1045-1048.
111. Chang, S. M.; Wen, P.; Cloughesy, T.; Greenberg, H.; Schiff, D.; Conrad, C.; Fink, K.; Robins, H. I.; De Angelis, L.; Raizer, J.; Hess, K.; Aldape, K.; Lamborn, K. R.; Kuhn, J.; Dancey, J.; Prados, M. D. Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest. New Drugs 2005, 23, 357-361.
112. Stallone, G.; Schena, A.; Infante, B.; Di Paolo, S.; Loverre, A.; Maggio, G.; Ranieri, E.; Gesualdo, L.; Schena, F. P.; Grandaliano, G. Sirolimus for Kaposi's sarcoma in renal-transplant recipients. N. Engl. J. Med. 2005, 352, 1317-1323.
113. Raymond, E.; Alexandre, J.; Faivre, S.; Vera, K.; Materman, E.; Boni, J.; Leister, C.; Korth-Bradley, J.; Hanauske, A.; Armand, J. P. Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J. Clin. Oncol. 2004, 22, 2336-2347.
114. Campistol, J. M.; Gutierrez-Dalmau, A.; Torregrosa, J. V. Conversion to sirolimus: A successful treatment for posttransplantation Kaposi's sarcoma. Transplantation 2004, 77, 760-762.
115. Atkins, M. B.; Hidalgo, M.; Stadler, W. M.; Logan, T. F.; Dutcher, J. P.; Hudes, G. R.; Park, Y.; Lion, S. H.; Marshall, B.; Boni, J. P.; Dukart, G.; Sherman, M. L. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J. Clin. Oncol. 2004, 22, 909-918.
116. 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. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 2007, 356, 2271-81.
117. Sarbassov, D. D.; Ali, S. M.; Sabatini, D. M. Growing roles for the mTOR pathway. Curr. Opin. Cell Biol. 2005, 17, 596-603.
118. Manning, B. D. Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. J. Cell Biol. 2004, 167, 399-403.
119. Sarbassov, D. D.; Guertin, D. A.; Ali, S. M.; Sabatini, D. M.
120. Sarbassov, D. D.; Ali, S. M.; Sengupta, S.; Sheen, J. H.; Hsu, P. P.; Bagley, A. F.; Markhard, A. L.; Sabatini, D. M. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Molecular Cell 2006, 22, 159-168.
121. Fan, Q. W.; Knight, Z. A.; Goldenberg, D. D.; Yu, W.; Mostov, K. E.; Stokoe, D.; Shokat, K. M.; Weiss, W. A. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 2006, 9, 341-349.
122. Raynaud, F. I.; Eccles, S.; Clarke, P. A.; Hayes, A.; Nutley, B.; Alix, S.; Henley, A.; Di-Stefano, F.; Ahmad, Z.; Guillard, S.; Bjerke, L. M.; Kelland, L.; Valenti, M.; Patterson, L.; Gowan, S.; Brandon, A. D.; Hayakawa, M.; Kaizawa, H.; Koizumi, T.; Ohishi, T.; Patel, S.; Saghir, N.; Parker, P.; Waterfield, M.; Workman, P. Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases. Cancer Res. 2007, 67, 5840-5850.
123. Whyte, D. B.; Holbeck, S. L. Correlation of PIK3Ca mutations with gene expression and drug sensitivity in NCI-60 cell lines. Biochem. Biophys. Res. Commun. 2006, 340, 469-475.
124. Saal, L. H.; Holm, K.; Maurer, M.; Memeo, L.; Su, T.; Wang, X. M.; Yu, J. S.; Malmstrom, P. O.; Mansukhani, M.; Enoksson, J.; Hibshoosh, H.; Borg, A.; Parsons, R. 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, 2554-2559.
125. Chan, C. T.; Metz, M. Z.; Kane, S. E. Differential sensitivities of trastuzumab (Herceptin (R))-resistant human breast cancer cells to phosphoinositide-3 kinase (PI-3K) and epidermal growth factor receptor (EGFR) kinase inhibitors. Breast Cancer Res. Treat. 2005, 91, 187-201.
126. Jordan, N. J.; Gee, J. M. W.; Barrow, D.; Wakeling, A. E.; Nicholson, R. I. Increased constitutive activity of PKB/Akt in tamoxifen resistant breast cancer MCF-7 cells. Breast Cancer Res. Treat. 2004, 87, 167-180.
127. Yakes, F. M.; Chinratanalab, W.; Ritter, C. A.; King, W.; Seelig, S.; Arteaga, C. L. Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Res. 2002, 62, 4132-4141.
128. Perez-Tenorio, G.; Stal, O. Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients. Br. J. Cancer 2002, 86, 540-545.