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RNAi-based screening of the human kinome identifies Akt-cooperating kinases: a new approach to designing efficacious multitargeted kinase inhibitors

Abstract

Tumors comprise genetically heterogeneous cell populations, whose growth and survival depend on multiple signaling pathways. This has spurred the development of multitargeted therapies, including small molecules that can inhibit multiple kinases. A major challenge in designing such molecules is to determine which kinases to inhibit in each cancer to maximize efficacy and therapeutic index. We describe an approach to this problem implementing RNA interference technology. In order to identify Akt-cooperating kinases, we screened a library of kinase-directed small interfering RNAs (siRNAs) for enhanced cancer cell killing in the presence of Akt inhibitor A-443654. siRNAs targeting casein kinase I gamma 3 (CSNK1G3) or the inositol polyphosphate multikinase (IPMK) significantly enhanced A-443654-mediated cell killing, and caused decreases in Akt Ser-473 and ribosomal protein S6 phosphorylation. Small molecules targeting CSNK1G3 and/or IPMK in addition to Akt may thus exhibit increased efficacy and have the potential for improved therapeutic index.

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References

  • Aza-Blanc P, Cooper CL, Wagner K, Batalov S, Deveraux QL, Cooke MP . (2003). Mol Cell 12: 627–637.

  • Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D . (2003). J Clin Invest 111: 1287–1295.

  • Blume-Jensen P, Hunter T . (2001). Nature 411: 355–365.

  • Caffrey JJ, Darden T, Wenk MR, Shears SB . (2001). FEBS Lett 499: 6–10.

  • Chang SC, Miller AL, Feng Y, Wente SR, Majerus PW . (2002). J Biol Chem 277: 43836–43843.

  • Cohen P . (2002). Nat Rev Drug Disc 1: 309–315.

  • Dai Y, Rahmani M, Corey SJ, Dent P, Grant S . (2004). J Biol Chem 279: 34227–34239.

  • Dancey J, Sausville EA . (2003). Nat Rev Drug Disc 2: 296–313.

  • Daub H, Specht K, Ullrich A . (2004). Nat Rev Drug Disc 3: 1001–1010.

  • Deininger MW, Druker BJ . (2004). Cancer Cell 6: 108–110.

  • Donato NJ, Wu JY, Stapley J, Gallick G, Lin H, Arlinghaus R et al. (2003). Blood 101: 690–698.

  • Druker BJ . (2002). Cancer Cell 1: 31–36.

  • Elbashir SM, Harborth J, Weber K, Tuschl T . (2002). Methods 26: 199–213.

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

  • Forsburg SL . (2003). Nat Rev Genet 2: 659–668.

  • Gonzalez B, Schell MJ, Letcher AJ, Veprintsev DB, Irvine RF, Williams RL . (2004). Mol Cell 15: 689–701.

  • Hanada M, Feng J, Hemmings Brian A . (2004). Biochim Biophys Acta 1697: 3–16.

  • Hanakahi LA, Bartlet-Jones M, Chappel C, Pappin D, West SC . (2000). Cell 102: 721–729.

  • Hanakahi LA, West SC . (2002). EMBO J 21: 2038–2044.

  • Hsieh AC, Bo R, Manola J, Vazquez F, Bare O, Khvorova A et al. (2004). Nucleic Acids Res 32: 893–901.

  • Jackson AL, Linsley PS . (2004). Trends Genet 20: 521–524.

  • Jackson AL, Bartz SR, Schelter J, Kobayashi SV, Burchard J, Mao M et al. (2003). Nat Biotechnol 21: 635–637.

  • Komander D, Fairservice A, Deak M, Kular GS, Prescott AR, Downes CP et al. (2004). EMBO J 23: 3918–3928.

  • Kusuda J, Hirai M, Toyoda A, Tanuma R, Hashimoto K . (1998). Cytogenet Cell Genet 83: 101–103.

  • Luo J, Manning BD, Cantley LC . (2003). Cancer Cell 4: 257–262.

  • Luo Y, Shoemaker AR, Liu X, Woods KW, Thomas SA, de Jong R et al. (2005). Mol Cancer Therap 4: 977–986.

  • Ma Y, Lieber MR . (2002). J Biol Chem 277: 10756–10759.

  • MacKeigan JP, Murphy LO, Blenis J . (2005). Nat Cell Biol 7: 591–600.

  • McKay RM, Peters JM, Graff JM . (2001). Dev Biol 235: 388–396.

  • Melnikova I, Golden J . (2004). Nat Rev Drug Disc 3: 993–994.

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

  • Mouritzen P, Nielsen PS, Jacobsen N, Noerholm M, Lomholt C, Pfundheller HM et al. (2004). BioTechniques 37: 492–495.

  • Nalaskowski MM, Deschermeier C, Fanick W, Mayr GW . (2002). Biochem J 366: 549–556.

  • Piccolo E, Vignati S, Maffucci T, Innominato PF, Riley AM, Potter BVL et al. (2004). Oncogene 23: 1754–1765.

  • Pietras K, Hanahan D . (2005). J Clin Oncol 23: 939–952.

  • Rane MJ, Coxon PY, Powell DW, Webster R, Klein JB, Pierce W et al. (2001). J Biol Chem 276: 3517–3523.

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

  • Scacheri PC, Rozenblatt-Rosen O, Caplen NJ, Wolfsberg TG, Umayam L, Lee JC et al. (2004). Proc Natl Acad SciUSA 101: 1892–1897.

  • Semizarov D, Frost L, Sarthy A, Kroeger P, Halbert DN, Fesik SW . (2003). Proc Natl Acad SciUSA 100: 6347–6352.

  • Shawver LK, Slamon D, Ullrich A . (2002). Cancer Cell 1: 117–123.

  • Shears SB . (2004). Biochem J 377: 265–280.

  • Vara J, Angel Fresno Casado E, de Castro J, Cejas P, Belda-Iniesta C, González-Barón M . (2004). Cancer 30: 193–204.

  • Verbsky JW, Chang S-C, Wilson MP, Mochizuki Y, Majerus PW . (2005). J Biol Chem 280: 1911–1920.

  • Vivanco I, Sawyers CL . (2002). Nat Rev Cancer 2: 489–501.

  • Wendel HG, De Stanchina E, Fridman Jordan S, Malina A, Ray S, Kogan S et al. (2004). Nature 428: 332–337.

  • York JD, Odom AR, Murphy R, Ives EB, Wente SR . (1999). Science 285: 96–100.

  • Zhai L, Graves PR, Robinson LC, Italiano M, Culbertson MR, Rowles J et al. (1995). J Biol Chem 270: 12717–12724.

  • Zhang JH, Chung TD, Oldenburg KR . (1999). J Biomol Screening 4: 67–73.

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Acknowledgements

We wish to thank Jameel Shah, Edward Han, Tom McGonigal, Xuesong Liu, Aparna Sarthy, Yu Shen, Zhihong Liu, and Philip Majerus for their insights and helpful discussions. We also thank Xiaoli Huang and Loren Lasko for technical assistance.

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Correspondence to J D Leverson.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

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Morgan-Lappe, S., Woods, K., Li, Q. et al. RNAi-based screening of the human kinome identifies Akt-cooperating kinases: a new approach to designing efficacious multitargeted kinase inhibitors. Oncogene 25, 1340–1348 (2006). https://doi.org/10.1038/sj.onc.1209169

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