Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

The Akt/PKB pathway: molecular target for cancer drug discovery

Abstract

The serine/threonine kinase Akt/PKB pathway presents an exciting new target for molecular therapeutics, as it functions as a cardinal nodal point for transducing extracellular (growth factor and insulin) and intracellular (receptor tyrosine kinases, Ras and Src) oncogenic signals. In addition, alterations of the Akt pathway have been detected in a number of human malignancies. Ectopic expression of Akt, especially constitutively activated Akt, is sufficient to induce oncogenic transformation of cells and tumor formation in transgenic mice as well as chemoresistance. Akt has a wide range of downstream targets that regulate tumor-associated cell processes such as cell growth, cell cycle progression, survival, migration, epithelial–mesenchymal transition and angiogenesis. Blockage of Akt signaling results in apoptosis and growth inhibition of tumor cells with elevated Akt. The observed dependence of certain tumors on Akt signaling for survival and growth has wide implications for cancer therapy, offering the potential for preferential tumor cell killing. In the last several years, through combinatorial chemistry, high-throughput and virtual screening, and traditional medicinal chemistry, a number of inhibitors of the Akt pathway have been identified. This review focuses on ongoing translational efforts to therapeutically target the Akt pathway.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  • Abraham RT . (2004). DNA Repair, 3, 883–887.

  • Adini I, Rabinovitz I, Sun JF, Prendergast GC and Benjamin LE . (2003). Genes Dev., 17, 2721–2732.

  • Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P and Hemmings BA . (1996). EMBO J., 15, 6541–6551.

  • Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB and Cohen P . (1997). Curr. Biol., 7, 261–269.

  • Altomare DA, Tanno S, De Rienzo A, Klein-Szanto AJ, Tanno S, Skele KL, Hoffman JP and Testa JR . (2003). J. Cell Biochem., 88, 470–476.

  • Altomare DA, Wang HQ, Skele KL, De Rienzo A, Klein-Szanto AJ, Godwin AK and Testa JR . (2004). Oncogene, 23, 5853–5857.

  • Altomare DA, You H, Xiao GH, Ramos-Nino ME, Skele KL, De Rienzo A, Jhanwar SC, Mossman BT, Kane AB and Testa JR . (2005). Oncogene [Epub ahead of print].

  • Altomare DA and Testa JR . (2005). Oncogene Rev., 24, 7455–7464.

  • Arcaro A and Wymann MP . (1993). Biochem. J., 269, 297–301.

  • Arlt A, Gehrz A, Muerkoster S, Vorndamm J, Kruse ML, Folsch UR and Schafer H . (2003). Oncogene, 22, 3243–3251.

  • Asnaghi L, Calastretti A, Bevilacqua A, D'Agnano I, Gatti G, Canti G, Delia D, Capaccioli S and Nicolin A . (2004). Oncogene, 23, 5781–5791.

  • Auguin D, Barthe P, Royer C, Stern MH, Noguchi M, Arold ST and Roumestand C . (2004). J. Biol. Chem., 279, 35890–35902.

  • Balendran A, Casamayor A, Deak M, Paterson A, Gaffney P, Currie R, Downes CP and Alessi DR . (1999). Curr. Biol., 9, 393–404.

  • Balsara BR, Pei J, Mitsuuchi Y, Page R, Klein-Szanto A, Wang H, Unger M and Testa JR . (2004). Carcinogenesis, 25, 2053–2059.

  • Barnett SF, Bilodeau MT and Lindsley CW . (2005a). Curr. Top Med. Chem., 5, 109–125.

  • Barnett SF, Defeo-Jones D, Fu S, Hancock PJ, Haskell KM, Jones RE, Kahana JA, Kral AM, Leander K, Lee LL, Malinowski J, McAvoy EM, Nahas DD, Robinson RG and Huber HE . (2005b). Biochem. J., 385, 399–408.

  • Bellacosa A, Testa JR, Staal SP and Tsichlis PN . (1991). Science, 254, 274–277.

  • Bellacosa A, de Feo D, Godwin AK, Bell DW, Cheng JQ, Altomare DA, Wan M, Dubeau L, Scambia G and Masciullo V et al. (1995). Int. J. Cancer, 64, 280–285.

  • Brazil DP, Park J and Hemmings BA . (2002). Cell, 111, 293–303.

  • Breitenlechner CB, Friebe WG, Brunet E, Werner G, Graul K, Thomas U, Kunkele KP, Schafer W, Gassel M, Bossemeyer D, Huber R, Engh RA and Masjost B . (2005). J. Med. Chem., 48, 163–170.

  • Burgering BMT and Coffer PJ . (1995). Nature, 376, 599−602.

  • Castillo SS, Brognard J, Petukhov PA, Zhang C, Tsurutani J, Granville CA, Li M, Jung M, West KA, Gills JG, Kozikowski AP and Dennis PA . (2004a). Cancer Res., 64, 2782–2792.

  • Castillo SS, Brognard J, Petukhov PA, Zhang C, Tsurutani J, Granville CA, Li M, Jung M, West KA, Gills JG, Kozikowski AP and Dennis PA . (2004b). Cancer Res., 64, 2782–2792.

  • Chan S . (2004). Br. J. Cancer, 91, 1420–1424.

  • Chan TO, Rittenhouse SE and Tsichlis PN . (1999). Annu. Rev. Biochem., 68, 965–1014.

  • Chen JS, Lan K and Hung MC . (2003). Drug Resist. Updat., 6, 129–136.

  • Chen WS, Xu PZ, Gottlob K, Chen ML, Sokol K, Shiyanova T, Roninson I, Weng W, Suzuki R, Tobe K, Kadowaki T and Hay N . (2001). Genes Dev., 15, 2203–2208.

  • Cheng JQ, Altomare DA, Klein MA, Lee WC, Kruh GD, Lissy NA and Testa JR . (1997). Oncogene, 14, 2793–2801.

  • Cheng JQ, Godwin AK, Bellacosa A, Taguchi T, Franke TF, Hamilton TC, Tsichlis PN and Testa JR . (1992). Proc. Natl. Acad. Sci. USA, 89, 9267–9271.

  • Cheng JQ, Jiang X, Fraser M, Li M, Dan HC, Sun M and Tsang BK . (2002). Drug Resist. Updat., 5, 131–146.

  • Cheng JQ, Ruggeri B, Klein WM, Sonoda G, Altomare DA, Watson DK and Testa JR . (1996). Proc. Natl. Acad. Sci. USA, 93, 3636–3641.

  • Cho H, Mu J, Kim JK, Thorvaldsen JL, Chu Q, Crenshaw III EB, Kaestner KH, Bartolomei MS, Shulman GI and Birnbaum MJ . (2001a). Science, 292, 1728–1731.

  • Cho H, Thorvaldsen JL, Chu Q, Feng F and Birnbaum MJ . (2001b). J. Biol. Chem., 276, 38349–38352.

  • Chung FL, Schram KH, Panzica RP, Earl RA, Wotring LL and Townsend LB . (1980). J. Med. Chem., 23, 1158–1166.

  • Clark M . (2000). Immunol. Today, 21, 397–402.

  • Cobb WR, Bogden AE, Reich SD, Griffin TW, Kelton DE and LePage DJ . (1983). Cancer Treat Rep., 67, 173–178.

  • Coffer PJ and Woodgett JR . (1991). Eur. J. Biochem., 201, 475–481.

  • Dan HC, Jiang K, Coppola D, Hamilton A, Nicosia SV, Sebti SM and Cheng JQ . (2004). Oncogene, 23, 706–715.

  • Datta K, Bellacosa A, Chan TO and Tsichlis PN . (1996). J. Biol. Chem., 271, 30835–30839.

  • Datta SR, Brunet A and Greenberg ME . (1999). Genes Dev., 13, 2905−2927.

  • DeFeo-Jones D, Barnett SF, Fu S, Hancock PJ, Haskell KM, Leander KR, McAvoy E, Robinson RG, Duggan ME, Lindsley CW, Zhao Z, Huber HE and Jones RE . (2005). Mol. Cancer Ther., 4, 271–279.

  • deGraffenried LA, Friedrichs WE, Russell DH, Donzis EJ, Middleton AK, Silva JM, Roth RA and Hidalgo M . (2004). Clin. Cancer Res., 10, 8059–8067.

  • Easton RM, Cho H, Roovers K, Shineman DW, Mizrahi M, Forman MS, Lee VM, Szabolcs M, de Jong R, Oltersdorf T, Ludwig T, Efstratiadis A and Birnbaum MJ . (2005). Mol. Cell Biol., 25, 1869–1878.

  • Edinger AL, Linardic CM, Chiang GG, Thompson CB and Abraham RT . (2003). Cancer Res., 63, 8451–8460.

  • Fan QW, Specht KM, Zhang C, Goldenberg DD, Shokat KM and Weiss WA . (2003). Cancer Res., 63, 8930–8938.

  • Feldman RI, Wu JM, Polokoff MA, Kochanny MJ, Dinter H, Zhu D, Biroc SL, Alicke B, Bryant J, Yuan S, Buckman BO, Lentz D, Ferrer M, Whitlow M, Adler M, Finster S, Chang Z and Arnaiz DO . (2005). J. Biol. Chem., 280, 19867–19874.

  • Feng J, Park J, Cron P, Hess D and Hemmings BA . (2004). J. Biol. Chem., 279, 41189–41196.

  • Feun LG, Blessing JA, Barrett RJ and Hanjani P . (1993). Am. J. Clin. Oncol., 16, 506–508.

  • Feun LG, Savaraj N, Bodey GP, Lu K, Yap BS, Ajani JA, Burgess MA, Benjamin RS, McKelvey E and Krakoff I . (1984). Cancer Res., 44, 3608–3612.

  • Finan PM and Thomas MJ . (2004). Biochem. Soc. Trans., 32, 378–382.

  • Fishwild DM, O'Donnell SL, Bengoechea T, Hudson DV, Harding F, Bernhard SL, Jones D, Kay RM, Higgins KM, Schramm SR and Lonberg N . (1996). Nat. Biotechnol., 14, 845–851.

  • Franke TF, Yang SL, Chan TO, Datta K, Kazlauskas A, Morrison DK, Kaplan DR and Tsichlis PN . (1995). Cell, 81, 727−736.

  • George S, Rochford JJ, Wolfrum C, Gray SL, Schinner S, Wilson JC, Soos MA, Murgatroyd PR, Williams RM, Acerini CL, Dunger DB, Barford D, Umpleby AM, Wareham NJ, Davies HA, Schafer AJ, Stoffel M, O'Rahilly S and Barroso I . (2004). Science, 304, 1325–1328.

  • Hiromura M, Okada F, Obata T, Auguin D, Shibata T, Roumestand C and Noguchi M . (2004). J. Biol. Chem., 279, 53407–53418.

  • Hoffman K, Holmes FA, Fraschini G, Esparza L, Frye D, Raber MN, Newman RA and Hortobagyi GN . (1996). Cancer Chemother. Pharmacol., 37, 254–258.

  • Hutchinson J, Jin J, Cardiff RD, Woodgett JR and Muller WJ . (2001). Mol. Cell Biol., 21, 2203–2212.

  • Jiang K, Coppola D, Crespo NC, Nicosia SV, Hamilton AD, Sebti SM and Cheng JQ . (2000). Mol. Cell. Biol., 20, 139–148.

  • Jiang K, Sun J, Cheng JQ, Djeu JY, Wei S and Sebti SM . (2004). Mol. Cell Biol., 24, 5565–5576.

  • Johnson MA and Pinto BM . (2002). Aust. J. Chem., 55, 13–25.

  • Jones PF, Jakubowicz T, Pitossi FJ, Maurer F and Hemmings BA . (1991). Proc. Natl. Acad. Sci. USA, 88, 4171–4175.

  • Kawakami Y, Nishimoto H, Kitaura J, Maeda-Yamamoto M, Kato RM, Littman DR, Rawlings DJ and Kawakami T . (2004). J. Biol. Chem., 279, 47720–47725.

  • Kim D, Dan HC, Park S, Yang L, Liu Q, Kaneko S, Ning J, He L, Yang H, Sun M, Nicosia SV and Cheng JQ . (2005). Front Biosci., 10, 975–987.

  • Knuefermann C, Lu Y, Liu B, Jin W, Liang K, Wu L, Schmidt M, Mills GB, Mendelsohn J and Fan Z . (2003). Oncogene, 22, 3205–3512.

  • Komander D, Kular GS, Bain J, Elliott M, Alessi DR and Van Aalten DM . (2003). Biochem. J., 375, 255–262.

  • Kondapaka SB, Singh SS, Dasmahapatra GP, Sausville EA and Roy KK . (2003). Mol. Cancer Ther., 2, 1093–1103.

  • Kozikowski AP, Kiddle JJ, Frew T, Berggren M and Powis G . (1995). J. Med. Chem., 38, 1053–1056.

  • Kumar CC and Madison V . (2005). Oncogene Rev., 24, 7493–7501.

  • Laine J, Kunstle G, Obata T, Sha M and Noguchi M . (2000). Mol. Cell., 6, 395–407.

  • Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH and Parsons R . (1997). Science, 275, 1943–1947.

  • Lindsley CW, Zhao Z, Leister WH, Robinson RG, Barnett SF, Defeo-Jones D, Jones RE, Hartman GD, Huff JR, Huber HE and Duggan ME . (2005). Bioorg. Med. Chem. Lett., 15, 761–764.

  • Liu A-X and Prendergast GC . (2000). FEBS Lett., 481, 205–208.

  • Liu A-X, Testa JR, Hamilton TC, Jove R, Nicosia SV and Cheng JQ . (1998). Cancer Res., 58, 2973−2977.

  • Luo Y, Smith RA, Guan R, Liu X, Klinghofer V, Shen J, Hutchins C, Richardson P, Holzman T, Rosenberg SH and Giranda VL . (2004). Biochemistry, 43, 1254–1263.

  • Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, McMahon LM, Manola J, Brugarolas J, McDonnell TJ, Golub TR, Loda M, Lane HA and Sellers WR . (2004). Nat. Med., 10, 594–601.

  • Majumder PK, Yeh JJ, George DJ, Febbo PG, Kum J, Xue Q, Bikoff R, Ma H, Kantoff PW, Golub TR, Loda M and Sellers WR . (2003). Proc. Natl. Acad. Sci. USA., 100, 7841–7846.

  • Malstrom S, Tili E, Kappes D, Ceci JD and Tsichlis PN . (2001). Proc. Natl. Acad. Sci. USA., 98, 14967–14972.

  • Mandal M, Kim S, Younes MN, Jasser SA, El-Naggar AK, Mills GB and Myers JN . (2005). Br. J. Cancer, 92, 1899–1905.

  • McCafferty J, Griffiths AD, Winter G and Chiswell DJ . (1990). Nature, 348, 552–554.

  • Mende I, Malstrom S, Tsichlis PN, Vogt PK and Aoki M . (2001). Oncogene, 20, 4419–4423.

  • Meric-Bernstam F and Mills GB . (2004). Semin. Oncol., 31, 10–17.

  • Migawa MT, Drach JC and Townsend LB . (2005). J. Med. Chem., 48, 3840–3851.

  • Mitsiades CS, Mitsiades N and Koutsilieris M . (2004). Curr. Cancer Drug Targets, 4, 235–256.

  • Mittelman A, Casper ES, Godwin TA, Cassidy C and Young CW . (1983). Cancer Treat Rep., 67, 159–162.

  • Mora A, Komander D, van Aalten DM and Alessi DR . (2004). Semin. Cell Dev. Biol., 15, 161–170.

  • Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, Hortobagyi GN, Hung MC and Yu D . (2004). Cancer Cell, 6, 117–127.

  • Parsons R . (2004). Semin Cell Dev. Biol., 15, 171–176.

  • Partovian C and Simons M . (2004). Cell Signal., 16, 951–957.

  • Pekarsky Y, Koval A, Hallas C, Bichi R, Tresini M, Malstrom S, Russo G, Tsichlis P and Croce CM . (2000). Proc. Natl. Acad. Sci. USA, 97, 3028–3033.

  • Persad S, Attwell S, Gray V, Mawji N, Deng JT, Leung D, Yan J, Sanghera J, Walsh MP and Dedhar S . (2001). J. Biol. Chem., 276, 27462–27469.

  • Powis G, Aksoy IA, Melder DC, Aksoy S, Eichinger H, Fauq AH and Kozikowski AP . (1991). Cancer Chemother. Pharmacol., 29, 95–104.

  • Powis G, Basseches PJ, Kroschel DM, Richardson RL, O'Connell MJ and Kvols LK . (1986). Cancer Treat Rep., 70, 359–362.

  • Prendergast GC . (2000). Curr. Opin. Cell Biol., 12, 166–173.

  • Rao RD, Buckner JC and Sarkaria JN . (2004). Curr. Cancer Drug Targets, 4, 621–635.

  • Remy I, Montmarquette A and Michnick SW . (2004). Nat. Cell Biol., 6, 358–365.

  • Reuveni H, Livnah N, Geiger T, Klein S, Ohne O, Cohen I, Benhar M, Gellerman G and Levitzki A . (2002). Biochemistry, 41, 10304–10314.

  • Sadhu C, Masinovsky B, Dick K, Sowell CG and Staunton DE . (2003). J. Immunol., 170, 2647–2654.

  • Sarbassov DD, Guertin DA, Ali SM and Sabatini DM . (2005). Science, 307, 1098–1101.

  • Sato S, Fujita N and Tsuruo T . (2002). Oncogene, 21, 1727–1738.

  • Schilcher RB, Haas CD, Samson MK, Young JD and Baker LH . (1986). Cancer Res., 46, 3147–3151.

  • Sebti SM and Der CJ . (2003). Nat. Rev. Cancer, 3, 945–951.

  • Semba S, Itoh N, Ito M, Harada M and Yamakawa M . (2002). Clin. Cancer Res., 8, 1957–1963.

  • Senderowicz AM . (2003a). Cancer Chemother. Pharmacol., 52, S61–S73.

  • Senderowicz AM . (2003b). Oncogene, 22, 6609–6620.

  • Shaw M, Cohen P and Alessi DR . (1998). Biochem. J., 336, 241−246.

  • Shin I, Edl J, Biswas S, Lin PC, Mernaugh R and Arteaga CL . (2005). Cancer Res., 65, 2815–2824.

  • Shintani T and Klionsky DJ . (2004). Science, 306, 990–995.

  • Staal SP, Hartley JW and Rowe WP . (1977). Proc. Natl. Acad. Sci. USA, 74, 3065–3067.

  • Staal SP . (1987). Proc. Natl. Acad. Sci. USA, 84, 5034–5037.

  • Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, Ruland J, Penninger JM, Siderovski DP and Mak TW . (1998). Cell, 95, 29−39.

  • Steck PA, Pershouse MA, Jasser SA, Yung WKA, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DHF and Tavtigian SV . (1997). Nat. Genet., 15, 356–362.

  • Sun M, Paciga JE, Feldman RI, Yuan Z, Coppola D, Lu YY, Shelley SA, Nicosia SV and Cheng JQ . (2001a). Cancer Res., 61, 5985–5991.

  • Sun M, Wang G, Paciga JE, Feldman RI, Yuan Z, Ma X, Shelley SA, Jove R, Tsichlis PN, Nicosia SV and Cheng JQ . (2001b). Am. J. Pathol., 159, 431–437.

  • Sun M, Yang L, Feldman RI, Sun XM, Bhalla KN, Jove R, Nicosia SV and Cheng JQ . (2003). J. Biol. Chem., 278, 42992–43000.

  • Tabellini G, Cappellini A, Tazzari PL, Fala F, Billi AM, Manzoli L, Cocco L and Martelli AM . (2005). J. Cell Physiol., 202, 623–634.

  • Testa JR and Bellacosa A . (2001). Proc. Natl. Acad. Sci. USA, 98, 10983–10985.

  • Toker A and Newton AC . (2000). J. Biol. Chem., 275, 8271–8274.

  • Tschopp O, Yang ZZ, Brodbeck D, Dummler BA, Hemmings-Mieszczak M, Watanabe T, Michaelis T, Frahm J and Hemmings BA . (2005). Development, 132, 2943–2954.

  • Van Ummersen L, Binger K, Volkman J, Marnocha R, Tutsch K, Kolesar J, Arzoomanian R, Alberti D and Wilding G . (2004). Clin. Cancer Res., 10, 7450–7456.

  • Vink SR, Schellens JH, van Blitterswijk WJ and Verheij M . (2005). Invest. New Drugs, 23, 279–286.

  • Vlahos CJ, Matter MF, Hui KY and Brown RF . (1994). J. Biol. Chem., 269, 5241–5248.

  • Wetzker R and Rommel C . (2004). Curr. Pharm. Des., 10, 1915–1922.

  • Wotring LL, Crabtree GW, Edwards NL, Parks Jr RE and Townsend LB . (1986). Cancer Treat Rep., 70, 491–497.

  • Wymann MP, Bulgarelli-Leva G, Zvelebil MJ, Pirola L, Vanhaesebroeck B, Waterfield MD and Panayatou G . (1996). Mol. Cell. Biol., 16, 1722–1733.

  • Yakes FM, Chinratanalab W, Ritter CA, King W, Seelig S and Arteaga CL . (2002). Cancer Res., 62, 4132–4141.

  • Yang J, Cron P, Thompson V, Good VM, Hess D, Hemmings BA and Barford D . (2002). Mol. Cell, 9, 1227–1240.

  • Yang L, Dan HC, Sun M, Liu Q, Sun XM, Feldman RI, Hamilton AD, Polokoff M, Nicosia SV, Herlyn M, Sebti SM and Cheng JQ . (2004). Cancer Res., 64, 4394–4399.

  • Yu D and Hung MC . (2000). Oncogene, 19, 6115–6121.

  • Yuan ZQ, Feldman RI, Sussman GE, Coppola D, Nicosia SV and Cheng JQ . (2003). J. Biol. Chem., 278, 23432–23440.

  • Yuan ZQ, Sun M, Feldman RI, Wang G, Ma X, Jiang C, Coppola D, Nicosia SV and Cheng JQ . (2000). Oncogene, 19, 2324–2330.

  • Zhao B, Bower MJ, McDevitt PJ, Zhao HZ, Davis ST, Johanson KO, Green SM, Concha NO and Zhou BBS . (2002). J. Biol. Chem., 277, 46609–46615.

  • Zhao Z, Leister WH, Robinson RG, Barnett SF, Defeo-Jones D, Jones RE, Hartman GD, Huff JR, Huber HE, Duggan ME and Lindsley CW . (2005). Bioorg. Med. Chem. Lett., 15, 905–909.

Download references

Acknowledgements

We thank Dr Joseph R Testa for his comments and critical reading. This work was supported by grants from the National Cancer Institute and Department of Defense (JQC).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jin Q Cheng.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cheng, J., Lindsley, C., Cheng, G. et al. The Akt/PKB pathway: molecular target for cancer drug discovery. Oncogene 24, 7482–7492 (2005). https://doi.org/10.1038/sj.onc.1209088

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209088

Keywords

This article is cited by

Search

Quick links