Advances of AKT pathway in human oncogenesis and as a target for anti-cancer drug discovery

Current Cancer Drug Targets

Volumn 8, Issue 1, 2008, Pages 2-6

  Cheng, George Z ^a   Park, Sungman ^b   Shu, Shaokun ^b   He, Lili ^b   Kong, William ^b   Zhang, Weizhou ^a   Yuan, Zengqiang ^c   Wang, Lu Hai ^a   Cheng, Jin Q ^b  

^a MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^b H LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE   (United States)

^c HARVARD MEDICAL SCHOOL   (United States)

Author keywords

AKT; Anti tumor target; Oncogene; Serine threonine kinase; Signal transduction; Small molecule inhibitor

Indexed keywords

ANTINEOPLASTIC AGENT; EPIDERMAL GROWTH FACTOR; INSULIN; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN KINASE B; PROTEIN SERINE THREONINE KINASE; PROTEIN TYROSINE KINASE; RAS ASSOCIATION DOMAIN FAMILY PROTEIN 1A; STEROID RECEPTOR COACTIVATOR 1;

ANGIOGENESIS; CARCINOGENESIS; CELL GROWTH; CELL MOTILITY; CELL SURVIVAL; HUMAN; NONHUMAN; ONCOGENE; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; ANTINEOPLASTIC AGENTS; DRUG DELIVERY SYSTEMS; DRUG DESIGN; HUMANS; NEOPLASMS; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION;

EID: 39049094092     PISSN: 15680096     EISSN: None     Source Type: Journal    
DOI: 10.2174/156800908783497159     Document Type: Review

References (42)

1. Staal, S. P.; Hartley, J. W.; Rowe, W. P. Isolation of transforming murine leukemia viruses from mice with a high incidence of spontaneous lymphoma. Proc. Natl. Acad. Sci. USA 1977, 74, 3065-3067.
2. Bellacosa, A.; Testa, J. R.; Staal, S. P.; Tsichlis, P. N. A retroviral oncogene, Akt, encoding a serine-threonine kinase containing an SH2-like region. Science 1991, 254, 274-277.
3. Cheng, J. Q.; Godwin, A. K.; Bellacosa, A.; Taguchi, T.; Franke, T. F.; Hamilton, T. C.; Tsichlis, P. N.; Testa, J. R. AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas. Proc. Natl. Acad. Sci. USA 1992, 89, 9267-9271.
4. Bellacosa, A.; de Feo, D.; Godwin, A. K.; Bell, D. W.; Cheng, J. Q.; Altomare, D. A.; Wan, M.; Dubeau, L.; Scambia, G.; Masciullo, V.; Ferrandina, G.; Benedetti, Panici. P.; Mancuso, S.; Neri, G.; Testa, J. R. Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int. J. Cancer 1995, 64, 280-285.
5. Cheng, J. Q.; Ruggeri, B.; Klein, W. M.; Sonoda, G.; Altomare, D. A.; Watson, D. K.; Testa, J. R. Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc. Natl. Acad. Sci. USA 1996, 93, 3636-3641.
6. Testa, J. R.; Tsichlis, P. N. Akt signaling in normal and malignant cells. Oncogene 2005, 24, 7391-7393.
7. Cheng, J. Q.; Altomare, D. A.; Klein, M. A.; Lee, W. C.; Kruh, G. D.; Lissy, N. A.; Testa, J. R. Transforming activity and mitosis-related expression of the AKT2 oncogene: evidence suggesting a link between cell cycle regulation and oncogenesis. Oncogene 1997, 14, 2793-2801.
8. Greenman, C.; Stephens, P.; Smith, R.; Dalgliesh, G. L.; Hunter, C.; Bignell, G.; Davies, H.; Teague, J.; Butler, A.; Stevens, C.; Edkins, S.; O'Meara, S.; Vastrik, I.; Schmidt, E. E.; Avis, T.; Barthorpe, S.; Bhamra, G.; Buck, G.; Choudhury, B.; Clements, J.; Cole, J.; Dicks, E.; Forbes, S.; Gray, K.; Halliday, K.; Harrison, R.; Hills, K.; Hinton, J.; Jenkinson, A.; Jones, D.; Menzies, A.; Mironenko, T.; Perry, J.; Raine, K.; Richardson, D.; Shepherd, R.; Small, A.; Tofts, C.; Varian, J.; Webb, T.; West, S.; Widaa, S.; Yates, A.; Cahill, D. P.; Louis, D. N.; Goldstraw, P.; Nicholson, A. G.; Brasseur, F.; Looijenga, L.; Weber, B. L.; Chiew, Y. E.; DeFazio, A.; Greaves, M. F.; Green, A. R.; Campbell, P.; Birney, E.; Easton, D. F.; Chenevix-Trench, G.; Tan, M. H.; Khoo, S. K.; The, B. T.; Yuen, S. T.; Leung, S. Y.; Wooster, R.; Futreal, P. A.; Stratton, M. R. Patterns of somatic mutation in human cancer genomes. Nature 2007, 446, 153-158.
9. Carpten, J. D.; Faber, A. L.; Horn, C.; Donoho, G. P.; Briggs, S. L.; Robbins, C. M.; Hostetter, G.; Boguslawski, S.; Moses, T. Y.; Savage, S.; Uhlik, M.; Lin, A.; Du, J.; Qian, Y. W.; Zeckner, D. J.; Tucker-Kellogg, G.; Touchman, J.; Patel, K.; Mousses, S.; Bittner, M.; Schevitz, R.; Lai, M. H.; Blanchard, K. L.; Thomas, J. E. A transforming mutation in the pleckstrin homology domain of Akt1 in cancer. Nature 2007, 448(7152), 439-444.
10. Altomare, D. A.; Testa, J. R. Perturbations of the Akt signaling pathway in human cancer. Oncogene 2005, 24, 7455-7464.
11. Irie, H. Y.; Pearline, R. V.; Grueneberg, D.; Hsia, M.; Ravichandran, P.; Kothari, N.; Natesan, S.; Brugge, J. S. Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition. J. Cell Biol. 2005, 171, 1023-1034.
12. 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. Mol. Cell. 2005, 20, 539-550.
13. Liu, H.; Radisky, D. C.; Nelson, C. M.; Zhang, H.; Fata, J. E.; Roth, R. A.; Bissell, M. J. Mechanism of Akt1 inhibition of breast cancer cell invasion reveals a protumorigenic role for TSC2. Proc. Natl. Acad. Sci. USA 2006, 103, 4134-4139.
14. Yang, J.; Mani, S. A.; Donaher, J. L.; Ramaswamy, S.; Itzykson, R. A.; Come, C.; Savagner, P.; Gitelman, I.; Richardson, A.; Weinberg, R. A. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 2004, 117, 27-39.
15. Cheng, G. Z.; Chan, J.; Wang, Q.; Zhang, W.; Sun, C. D.; Wang, L. H. Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel. Cancer Res. 2007, 67, 1979-1987.
16. Hutchinson, J.; Jin, J.; Cardiff, R. D.; Woodgett, J. R.; Muller, W. J. Activation of Akt (protein kinase B) in mammary epithelium provides a critical cell survival signal required for tumor progression. Mol. Cell Biol. 2001, 21, 2203-2212.
17. Maroulakou, I. G.; Oemler, W.; Naber, S. P.; Tsichlis, P. N. Akt1 ablation inhibits, whereas Akt2 ablation accelerates, the development of mammary adenocarcinomas in mouse mammary tumor virus (MMTV)-ErbB2/neu and MMTV-polyoma middle T transgenic mice. Cancer Res. 2007, 67, 167-177.
18. rd.; 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 (PKBβ). Science 2001, 292, 1728-1731.
19. 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.
20. Easton, R. M.; Cho, H.; Roovers, K.; Shineman, D. W.; Mizrahi, M.; Forman, M. S.; Lee, V. M.; Szabolcs, M.; de Jong, R.; Oltersdorf, T.; Ludwig, T.; Efstratiadis, A.; Birnbaum, M. J. Role for Akt3/protein kinase Bgamma in attainment of normal brain size. Mol. Cell Biol. 2005, 25, 1869-1878.
21. Dummler, B.; Tschopp, O.; Hynx, D.; Yang, Z. Z.; Dirnhofer, S.; Hemmings, B. A. Life with a single isoform of Akt: mice lacking Akt2 and Akt3 are viable but display impaired glucose homeostasis and growth deficiencies. Mol. Cell Biol. 2006, 26, 8042-8051.
22. Datta, S. R.; Brunet, A.; Greenberg, M. E. Cellular survival: a play in three Akts. Genes Dev. 1999, 13, 2905-2927.
23. Hennessy, 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 Discov. 2005, 4, 988-1004.
24. Li, J.; Yen, C.; Liaw, D.; Podsypanina, K.; Bose, S.; Wang, S. I.; Puc, J.; Miliaresis, C.; Rodgers, L.; McCombie, R.; Bigner, S. H.; Giovanella, B. C.; Ittmann, M.; Tycko, B.; Hibshoosh, H.; Wigler, M. H.; Parsons, R. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997, 275, 1943-1947.
25. Gao, T.; Furnari, F.; Newton, A. C. PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Mol. Cell 2005, 18, 13-24.
26. Brognard, J.; Sierecki, E.; Gao, T.; Newton, A. C. PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Mol. Cell 2007, 25, 917-931.
27. Cheng, J. Q.; Lindsley, C. W.; Cheng, G. Z.; Yang, H.; Nicosia, S. V. The Akt/PKB pathway: molecular target for cancer drug discovery. Oncogene 2005, 24, 7482-7492.
28. Granville, C. A.; Memmott, R. M.; Gills, J. J.; Dennis, P. A. Handicapping the race to develop inhibitors of the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin pathway. Clin. Cancer Res. 2006, 12(3 Pt 1), 679-689.
29. 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.
30. 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.
31. Castillo, S. S.; Brognard, J.; Petukhov, P. A.; Zhang, C.; 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.
32. 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.
33. Luo, Y.; Shoemaker, A. R.; Liu, X.; Woods, K. W.; Thomas, S. A.; de Jong, R.; Han, E. K.; Li, T.; 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, 977-986.
34. Lindsley, C. W.; Zhao, Z.; 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.
35. Yang, L.; Dan, H. C.; Sun, M.; Liu, Q.; 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.
36. Kayser, K. J.; Glenn, M. P.; Sebti, S. M.; Cheng, J. Q.; Hamilton, A. D. Modifications of the GSK3beta substrate sequence to produce substratemimetic inhibitors of Akt as potential anti-cancer therapeutics. Bioorg. Med. Chem. Lett. 2007, 17, 2068-2073.
37. DeFeo-Jones, D.; Barnett, S. F.; Fu, S.; Hancock, P. J.; Haskell, K. M.; Leander, K. R.; McAvoy, E.; Robinson, R. G.; Duggan, M. E.; Lindsley, C. W.; Zhao, Z.; Huber, H. E.; Jones, R. E. Tumor cell sensitization to apoptotic stimuli by selective inhibition of specific AKT/PKB family members. Mol. Cancer Ther. 2005, 4, 271-279.
38. 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. 1993, 16, 506-508.
39. Hoffman, K.; Holmes, F. A.; Fraschini, G.; Esparza, L.; Frye, D.; Raber, M. N.; Newman, R. A.; Hortobagyi, G. N. Phase I-II study: triciribine (tricyclic nucleoside phosphate) for metastatic breast cancer. Cancer Chemother. Pharmacol. 1996, 37, 254-258.
40. Argiris, A.; Cohen, E.; Karrison, T.; Esparaz, B.; Mauer, A.; Ansari, R.; Wong, S.; Lu, Y.; Pins, M.; Dancey, J.; Vokes, E. A phase II trial of perifosine, an oral alkylphospholipid, in recurrent or metastatic head and neck cancer. Cancer Biol. Ther. 2006, 5, 766-770.
41. Knowling, M.; Blackstein, M.; Tozer, R.; Bramwell, V.; Dancey, J.; Dore, N.; Matthews, S.; Eisenhauer, E. A phase II study of perifosine (D-21226) in patients with previously untreated metastatic or locally advanced soft tissue sarcoma: A National Cancer Institute of Canada Clinical Trials Group trial. Invest. New Drugs. 2006, 24, 435-439.
42. Marsh Rde, W.; Rocha Lima, C. M.; Levy, D. E.; Mitchell, E. P.; Rowland, K. M. Jr.; Benson, A. B. 3rd. A phase II trial of perifosine in locally advanced, unresectable, or metastatic pancreatic adenocarcinoma. Am. J. Clin. Oncol. 2007, 30, 26-31.