Druggable Signaling Proteins

  • Mouldy Sioud
  • Marianne Leirdal
Part of the Methods in Molecular Biology™ book series (MIMB, volume 361)


In normal cells, signaling pathways are tightly regulated. However, when they are aberrantly activated, certain pathways are capable of causing diseases. In many tumors, the aberrantly activated signaling proteins include members of the epidermal growth factor receptor family, the Ras proteins, protein kinase C isoenzymes, BCR-ABL fusion protein as well as transcription factors such as signal transducers and activators of transcriptions and Myc. Accordingly, deregulation of these signaling proteins holds promise for the development of new anticancer drugs. Studies in vitro and in disease-relevant models demonstrated that blocking the activation of a key target in a constitutively activated signaling pathway could reverse disease phenotype. Moreover, constitutive activation of the target alone is sufficient to induce relevant disease phenotype. Notably, the most dramatic therapeutic advances in cancer therapy during the last decade have come from agents targeted against active thyrosine kinases. These include imatinib (anti-BCR-ABL), gefitinib (anti-EGF receptor), and herpetin (anti-ErbB-2). Here, some selected validated and drugable targets are summarized.

Key Words

Signaling pathways Ras proteins BCR-ABL kinase STAT proteins PKC EGF receptor MAP kinases 


  1. 1.
    Shawver, L. K., Slamon, D., and Ullrich, A. (2002) Smart drugs: tyrosine kinase inhibitors in cancer therapy. Cancer Cell 1, 117–123.CrossRefPubMedGoogle Scholar
  2. 2.
    Levitzki, A. (1994) Signal-transduction therapy. Eur. J. Biochem. 226, 1–13.CrossRefPubMedGoogle Scholar
  3. 3.
    Dhanasekaran, N. (1998) Cell signaling: an overview. Oncogene 17, 1329–1330.CrossRefPubMedGoogle Scholar
  4. 4.
    Schlessinger, J. (2000) Cell signaling by receptor tyrosine kinases. Cell 103, 211–225.CrossRefPubMedGoogle Scholar
  5. 5.
    Mendelsohn, J. and Baselga, J. (2000) The EGF receptor family as targets for cancer therapy. Oncogene 19, 6550–6565.CrossRefPubMedGoogle Scholar
  6. 6.
    Campbell, L., Khosravi-Far, R., Rossmann, K. L., Clark, G. J., and Der, C. J. (1998) Increasing complexity of Ras signaling. Oncogene 17, 1395–1413.CrossRefPubMedGoogle Scholar
  7. 7.
    Manning, G., Whyte, D. B., Martinez, R., Hunter, T., and Sudarsanam, S. (2002) The protein kinase complement of the human genome. Science 298, 1912–1934.CrossRefPubMedGoogle Scholar
  8. 8.
    Roskoski, R. (2004) The ErbB/HER receptor protein-tyrosine kinases and cancer. Bioch. Biophys. Res. Commun. 319, 1–11.CrossRefGoogle Scholar
  9. 9.
    Bowman, T., Garcia, R., Turkson, R., and Jove, R. (2000) STATs in oncogenesis. Oncogene 19, 2474–2488.CrossRefPubMedGoogle Scholar
  10. 10.
    Bromberg, J. F., Horvath, C. M., Besser, D., Lathem, W. W., and Darnell, J. E., Jr. (1998) Mol. Cell. Biol. 18, 2553–2558.PubMedGoogle Scholar
  11. 11.
    Bromberg, J. F., Wrzeszczynska, M. H., Devgan, G., et al. (1999) Stat3 as an oncogene. Cell 98, 295–303.CrossRefPubMedGoogle Scholar
  12. 12.
    Polakis, P. (2000) Wnt signalling and cancer. Genes Devel. 14, 1837–1851.PubMedGoogle Scholar
  13. 13.
    Kinzler, K. W. and Vogelstein, B. (1996) Lessons from hereditary colorectal cancer. Cell 87, 159–170.CrossRefPubMedGoogle Scholar
  14. 14.
    Dekker, L. V. and Parker, P. J. (1994) Protein kinase C—a question of specificity. TIBS 19, 73–77.PubMedGoogle Scholar
  15. 15.
    Hug, H. and Sarre, T. F. (1993) Protein kinase C isoenzymes: divergence in signal transduction? Biochem. J. 291, 329–343.PubMedGoogle Scholar
  16. 16.
    Tsujimoto, Y. and Shimizu, S. (2000) Bcl-2 family: life-or-death switch. FEBS Letters 466, 6–10.CrossRefPubMedGoogle Scholar
  17. 17.
    Simonian, P. L., Grillot, D. A., and Nunez, G. (1997) Bcl-2 and Bcl-xL can differentially block chemotherapy-induced cell death. Blood 90, 1208–1216.PubMedGoogle Scholar
  18. 18.
    Dole, M., Nunez, G., Merchant, A. K., et al. (1994) Bcl-2 inhibits chemotherapy-induced apoptosis in neuroblastoma. Cancer Res. 54, 3253–3259.PubMedGoogle Scholar
  19. 19.
    Arteaga, C. L. (2001) The epidermal growth factor receptor: From mutant oncogene in nonhuman cancers to therapeutic target in human neoplasia. J. Clin. Oncol. 19, S32–S40.Google Scholar
  20. 20.
    Nicholson, R. I., Gee, J. M., and Harper, M. E. (2001) EGFR and cancer prognosis. Eur. J. Cancer 37, 9–15.CrossRefGoogle Scholar
  21. 21.
    Cooke, T., Reeves, J., Lannigan, A., and Stanton, P. (2001) The value of the human epidermal growth factor receptor-2 (Her-2) as a prognostic marker. Eur. J. Cancer. 37, 3–10.CrossRefPubMedGoogle Scholar
  22. 22.
    Chakravarti, A. Dicker, A., and Mehta, M. (2004) The contribution of epidermal growth factor receptor (EGFR) signaling pathway to radioresistance in human gliomas: a review of preclinical and correlative clinical data. Int. J. Rad. Oncol. Biol. Phys. 58, 927–931.CrossRefGoogle Scholar
  23. 23.
    Wong, A. J., Ruppert, J. M., Bigner, S. H., et al. (1992) Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc. Natl. Acad. Sci. USA 89, 2965–2969.CrossRefPubMedGoogle Scholar
  24. 24.
    Humphrey, P. A., Wong, A. J., Vogelstein, B., et al. (1990) Anti-synthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastoma. Proc. Natl. Acad. Sci. USA 87, 4207–4211.CrossRefPubMedGoogle Scholar
  25. 25.
    Hung, M.-C. and Lau, Y.-K. (1999) Basic science of HER-2/neu: A Review. Semin. Oncol. 26, 51–59.PubMedGoogle Scholar
  26. 26.
    Amundadottir, L. T. and Leder, P. (1998) Signal transduction pathways activated and required for mammary carcinogenesis in response to specific oncogenes. Oncogene 16, 737–746.CrossRefPubMedGoogle Scholar
  27. 27.
    Vignot, S., Faivre, S., Aguirre, D., and Raymond, E. (2005) mTOR-targeted therapy of cancer with rapamycin derivatives. Ann. Oncol. 16, 525–537.CrossRefPubMedGoogle Scholar
  28. 28.
    Mass, R. D. (2004) The HER receptor family: a rich target for therapeutic development. Int. J. Rad. Oncol. Biol. Phys. 58, 932–940.CrossRefGoogle Scholar
  29. 29.
    Willems, A., Gauger, K., Henrichs, C., and Harbeck, N. (2005) Antibody therapy for breast cancer. Anticancer Res. 25, 1483–1489.PubMedGoogle Scholar
  30. 30.
    Sebti, S. M. and Hamilton, A. D. (2000) Design of growth factor antagonists with antiangiogenic and antitumor properties. Oncogene 19, 6566–6573.CrossRefPubMedGoogle Scholar
  31. 31.
    Deininger, M., Goldman, J., and Melo, J. (2000) The molecular biology of chronic myeloid leukaemia. Blood 96, 3343–3356.PubMedGoogle Scholar
  32. 32.
    Bartram, C., de Klein, A., and Hagemeijer, A. (1983) Translocation of c-abl oncogene correlates with the presence of the Philadelphia chromosome in chronic myelocytic leukemia. Nature 306, 277–280.CrossRefPubMedGoogle Scholar
  33. 33.
    Bos, J. L. (1989) Ras oncogenes in human cancer. Cancer Res. 49, 4682–4689.PubMedGoogle Scholar
  34. 34.
    Adjei, A. A. (2001) Blocking oncogenic Ras signaling for cancer therapy. J. Natl. Cancer Inst. 93, 1062–1074.CrossRefPubMedGoogle Scholar
  35. 35.
    Johnston, S. R. (2001) Farnesyltransferase inhibitors: a novel targeted therapy for cancer. Lancet Oncol. 2, 18–26.CrossRefPubMedGoogle Scholar
  36. 36.
    De Bono, J. S. and Rowinsky, E. K. (2002) Therapeutics targeting signal transduction for patients with colorectal carcinoma. Br. Med. Bulletin. 64, 227–254.CrossRefGoogle Scholar
  37. 37.
    Cowsert, L. M. (1997) In vitro and in vivo activity of antisense inhibitors of ras: potential for clinical development. Anticancer Drug. Des. 12, 359–371.PubMedGoogle Scholar
  38. 38.
    Monia, B. P., Ecker, D. J., Zounes, M. A., Lima, W. F., and Freier, S. M. (1992) Selective inhibition of mutant Ha-Ras mRNA expression by antisense oligonucleotides. J. Biol. Chem. 267, 19,954–19,962.PubMedGoogle Scholar
  39. 39.
    Callans, L. S., Naama, H., Khandelwal, M., Plotkin, R., and Jardines, L. (1995) Raf-1 protein expression in human breast cancer cells. Ann. Surg. Oncol. 2, 38–42.CrossRefPubMedGoogle Scholar
  40. 40.
    Sithanandam, G., Dean, M., Brennscheidt, U., et al. (1989) Loss of heterozygosity of the c-raf locus in small cell lung carcionoma. Oncogene 4, 451–455.PubMedGoogle Scholar
  41. 41.
    Morrison, D. K. and Cutler, R. E. (1997) The complexity of Raf-1 regulation. Curr. Opin. Cell. Biol. 9, 174–179.CrossRefPubMedGoogle Scholar
  42. 42.
    Marquardt, B., Frith, D., and Stabel, S. (1994) Signalling from TPA to MAP kinase requires protein kinase C, raf and MEK: reconstitution of the signalling pathway in vitro. Oncogene 9, 3213–3218.PubMedGoogle Scholar
  43. 43.
    Lyons, J. F., Wilhelm, S., Hibner, B., and Bollag, G. (2001) Discovery of a novel Raf kinase inhibitor. Endocr. Relat. Cancer 8, 219–225.CrossRefPubMedGoogle Scholar
  44. 44.
    Iversen, P. O., Emanuel, P. D., and Sioud, M. (2002) Targeting Raf-1 gene expression by a DNA enzyme inhibits juvenile myelomonocytic leukemia cell growth. Blood 99, 4147–4153.CrossRefPubMedGoogle Scholar
  45. 45.
    Monia, B. P., Johnston, J. F., Geiger, T., Muller, M., and Fabbro, D. (1996) Antitumor activity of phosphorothioate antisense oligodeoxynucleotide targeted against c-Raf kinase. Nat. Med. 2, 668–675.CrossRefPubMedGoogle Scholar
  46. 46.
    Sebolt-Leopold, J. S. (2000) Development of anticancer drugs targeting the MAP kinase pathway. Oncogene 19, 6594–6599.CrossRefPubMedGoogle Scholar
  47. 47.
    Dudley, D. T., Pang, L., Decker, S. J., Bridges, A. J., and Saltiel, A. R. (1995) A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc. Natl. Acad. Sci. USA 92, 7686–7689.CrossRefPubMedGoogle Scholar
  48. 48.
    Sebolt-Leopold, J. S., Dudley, D. T., Herrera, R., et al. (1999) Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat. Med. 5, 810–816.CrossRefPubMedGoogle Scholar
  49. 49.
    Schaeffer, H. J. and Weber, M. J. (1999) Mitogen-activated protein kinases: specific messages from ubiquitous messengers. Mol. Cell. Biol. 19, 2435–2444.PubMedGoogle Scholar
  50. 50.
    Boulton, G., Nye, S. H., Robbibs, D. J., et al. (1991) ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin. Cell 65, 663–675.CrossRefPubMedGoogle Scholar
  51. 51.
    Plattner, R., Gupta, S., Khosravi-Far, R., et al. (1999) Differential contribution of the ERK and JNK mitogen-activated protein kinase cascades to ras transformation of HT1080 fibrosarcoma and DLD-1 colon carcinoma cells. Oncogene 18, 1807–1817.CrossRefPubMedGoogle Scholar
  52. 52.
    Silvany, R. E., Eliazer, S., Wolff, N. C., and Ilaria, R. L., Jr. (2000) Interference with the constitutive activation of ERK1 and ERK2 impairs EWS/FLI-1-dependent transformation. Oncogene 19, 4523–4530.CrossRefPubMedGoogle Scholar
  53. 53.
    Silvennoinen, O., Ihle, J. N., Schlessinger, J., and Levy, D. E. (1993) Interferon-induced nuclear signaling by Jak protein tyrosine kinases. Nature 366, 583–585.CrossRefPubMedGoogle Scholar
  54. 54.
    O’Shea, J. J., Gadina, M., and Schreiber, R. D. (2002) Cytokine signaling in 2002: new surprises in the JAK/STAT pathway. Cell 109, S121–S131.CrossRefPubMedGoogle Scholar
  55. 55.
    Schindler, C. W. (2002) JAK-STAT signaling in human disease. J. Clin. Invest. 109, 1133–1137.PubMedGoogle Scholar
  56. 56.
    Chen, X., Bhandari, R., Vinkermeier, U., Van Den Akker, F., Darnell, J. E., Jr., and Kuriyan, J. (2003) A reinterpretation of the dimerization interface of the N-terminal domains of STATs. Protein Sci. 12, 361–365.CrossRefPubMedGoogle Scholar
  57. 57.
    Luo, C. and Laaja, P. (2004) Inhibitors of JAKs/STATs and the kinases: a possible new cluster of drugs. DDT 9, 268–275.PubMedGoogle Scholar
  58. 58.
    Bromberg, J. F., Horvath, C. M., Besser, D., Lathem, W. W., and Darnell, J. E., Jr. (1998) Stat 3 activation is required for cellular transformation by v-src. Mol. Cell. Biol. 18, 2553–2558.PubMedGoogle Scholar
  59. 59.
    Turkson, J. and Jove, R. (2000) STAT proteins: novel molecular targets for cancer drug discovery. Oncogene 19, 6613–6626.CrossRefPubMedGoogle Scholar
  60. 60.
    Calo, V., Migliavacca, M., Bazan, V., et al. (2003) STAT proteins: from normal control of cellular events to tumorigenesis. J. Cell. Physiol. 197, 157–168.CrossRefPubMedGoogle Scholar
  61. 61.
    Turkson, J., Ryan, D., Kim, J. S., et al. (2001) Phosphotyrosyl peptides block Stat3-mediated DNA-binding activity, gene regulation, and cell transformation. J. Biol. Chem. 276, 45,443–45,455.CrossRefPubMedGoogle Scholar
  62. 62.
    Nishizuka, Y. (1992) Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 258, 607–614.CrossRefPubMedGoogle Scholar
  63. 63.
    Kikkawa, U., Takai, Y., Tanaka, Y., Miyake, R., and Nishizuka, Y. (1983) Protein kinase C as a possible receptor protein of tumor-promoting phorbol esters. J. Biol. Chem. 258, 11,442–11,445.PubMedGoogle Scholar
  64. 64.
    Blumberg, P. M. (1988) Protein kinase C as the receptor for the phorbol ester tumor promoters: sixth roads memorial award lecture. Cancer Res. 48, 1–8.PubMedGoogle Scholar
  65. 65.
    Rocha, A. B., Mans, D. R. A., Regner, A., and Schwartsmann, G. (2002) Targeting protein kinase C: new terapeutic opportunities against high-grade malignant gliomas. The Oncologist 7, 17–33.CrossRefPubMedGoogle Scholar
  66. 66.
    Sioud, M. and Sørensen, D. R. (1998) A nuclease-resistant protein kinase C alpha ribozyme blocks glioma cell growth. Nat. Biotechnol. 16, 556–561.CrossRefPubMedGoogle Scholar
  67. 67.
    Leirdal, M. and Sioud, M. (1999) Ribozyme inhinition of the protein kinase Ca triggers apoptosis in glioma cells. Br. J. Cancer. 80, 1558–1564.CrossRefPubMedGoogle Scholar
  68. 68.
    Sioud, M. and Leirdal, M. (2000) Design of nuclease resistant protein kinase Ca DNA enzymes with potential therapeutic application. J. Mol. Biol. 296, 937–947.CrossRefPubMedGoogle Scholar
  69. 69.
    Geiger, T., Muller, M., Dean, N. M., and Fabbro, D. (1998) Antitumor activity of a PKC-alpha antisense oligonucleotide in combination with standard chemotherapeutic agents against various human tumors transplanted into nude mice. Anticancer Drug Des. 13, 35–45.PubMedGoogle Scholar
  70. 70.
    Reed, J. C. (1998) Bcl-2 family proteins. Oncogene 17, 3225–3236.CrossRefPubMedGoogle Scholar
  71. 71.
    Zamzami, N., Brenner, C., Marzo, I., Susin, S. A., and Kroemer, G. (1998) Subcellular and submitochondrial mode of action of Bcl-2-like oncoproteins. Oncogene 16, 2265–2282.CrossRefPubMedGoogle Scholar
  72. 72.
    Muchmore, S. W., Sattler, M., Liang, H., et al. (1996) X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death Nature 381, 335–341.CrossRefPubMedGoogle Scholar
  73. 73.
    Oltersdorf, T., Elmore, S. W., Shoemaker, A. R., et al. (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435, 677–681.CrossRefPubMedGoogle Scholar
  74. 74.
    Ziegler, A., Luedke, G. H., Fabbro, D., Altmann, K. H., Stahel, R. A., and Zangemeister-Wittke, U. (1997) A novel antisense oligonucleotide targeting the coding region of the bcl-2_mRNA is a potent inducer of apoptosis in small cell lung cancer cells. J. Natl. Cancer Inst. 89, 1027–1036.CrossRefPubMedGoogle Scholar
  75. 75.
    Leech, S. H., Olie, R. A., Gautschi, O., et al. (2000) Induction of apoptosis in lung cancer cells following bcl-xL antisense treatment. Int. J. Cancer. 86, 570–576.CrossRefPubMedGoogle Scholar
  76. 76.
    Simoes-Wust, A., Schurpf, T., Hall, J., Stahel, R. A., and Zangmeister-wittke, U. (2002) Bcl-2/bcl-xL bispecific antisense treatment sensitizes breast carcinoma cells to doxorubicin, paclitaxel and cyclophosphoamide. Breast. Cancer. Res. Treat. 76, 157–166.CrossRefPubMedGoogle Scholar
  77. 77.
    Liotta, L. A. and Kohn, E. C. (2001) The microenvironment of the tumour-host interface. Nature 411, 375–379.CrossRefPubMedGoogle Scholar
  78. 78.
    Aharinejad, S., Paulus, P., Sioud, M., et al. (2004) Colony-stimulating factor-1 blockage by antisense oligonucleotides and small-interfering RNAs suppresses growth of human mammary tumor xenografts in mice. Caner Res. 64, 5378–5384.CrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  • Mouldy Sioud
    • 1
  • Marianne Leirdal
    • 2
  1. 1.Department of Immunology, Institute for Cancer ResearchThe Norwegian Radium Hospital, University of OsloOsloNorway
  2. 2.Molecular Medicine GroupInstitute of Cancer ResearchOsloNorway

Personalised recommendations