From Tyrphostins to Iressa and Gleevec: Signal Transduction Therapy from Concept to the Patient Bed

  • Alexander Levitzki
  • Dina Ben-Yehudah
Conference paper
Part of the NATO Science Series book series (NAII, volume 129)


Protein tyrosine kinases (PTK’s) is a unique family of protein kinases, whose members are all involved in intercellular and intracellular communications. They were the first family of proteins whose aberrant activities have been directly related to human malignancies. Therefore, they became the first set of novel therapeutic targets for the development of “signal transduction therapy”. The goal of this therapy is to manipulate aberrant signal transduction pathways in order to bring the demise of the cancer cell Since protein tyrosine kinases (PTKs) play a major role in driving cancer cells and lending them their anti-apoptotic robustness they were identified as targets for drug development. Tyrosine phosphorylation inhibitors (tyrphostins) were developed with the aim of blocking the enhanced signaling of PTK’s in cancer cells, and thus induce their apoptotic death. The principles of the approach, its successes and failures are discussed.


Chronic Myeloid Leukemia Chronic Myelogenous Leukemia Gastrointestinal Stromal Tumor Cytogenetic Response Complete Cytogenetic Response 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Allander.
    S. V., Nupponen, N. N., Ringner, M., Hostetter, G., Maher, G. W., Goldberger, N., Chen, Y., Carpten, J., Elkahloun, A. G., and Meltzer, P. S. (2001). Gastrointestinal stromal tumors with KIT mutations exhibit a remarkably homogeneous gene expression profile. Cancer Res 61, 8624–8628.Google Scholar
  2. Anafi.
    M., Gazit, A., Gilon, C, Ben-Neriah, Y., and Levitzki, A. (1992). Selective interactions of transforming and normal abl proteins with ATP, tyrosine-copolymer substrates, and tyrphostins. J Biol Chem 267, 4518–4523.Google Scholar
  3. Anafi.
    M, Gazit A., Gilon C, Neriah Y. B., and Levitzki A. (1993a). Tyrphostin-induced differentiation of mouse erythroleukemia cells. FEBS Lett 330, 260–264.CrossRefGoogle Scholar
  4. Anafi M, Gazit A., Zehavi A., Ben-Neriah Y., and Levitzki A. (1993b). Tyrphostin-induced inhibition of p210bcr-abl tyrosine kinase activity induces K562 to differentiate. Blood 82, 3524–3Google Scholar
  5. Barthe, C, Cony-Makhoul, P., Melo, J. V., and Mahon, J. R. (2001). Roots of clinical resistance to STI-571 cancer therapy. Science 293, 2163.Google Scholar
  6. Benhar.
    M., Engelberg D., and Levitzki A. (2002). ROS, stress-activated kinases and stress signaling in cancer. EMBO Rep 3, 420–425.CrossRefGoogle Scholar
  7. Buchdunger E., Zimmermann J., Mett H., Meyer T., Muller M., Druker B. J., and Lydon N. B. (1996). Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res 56, 100-104.Google Scholar
  8. Carlo-Stella.
    C, Regazzi, E., Sammarelli, G., Colla, S., Garau, D., Gazit, A., Savoldo, B., Cilloni, D., Tabilio, A., Levitzki, A., and Rizzoli, V. (1999). Effects of the tyrosine kinase inhibitor AG957 and an Anti-Fas receptor antibody on CD34(+) chronic myelogenous leukemia progenitor cells. Blood 93, 3973–3982Google Scholar
  9. Catlett-Falcone.
    R., Landowski T. H., Oshiro M. M., Turkson J., Levitzki A., Savino R., Ciliberto G., Moscinski L., Fernandez-Luna J. L., Nunez G.,. et al (1999). Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10, 105–115CrossRefGoogle Scholar
  10. Corbin.
    A. S., Buchdunger, E., Pascal, F., and Druker, B. J. (2002). Analysis of the structural basis of specificity of inhibition of the Abl kinase by STI571. J Biol Chem 277, 32214–32219.CrossRefGoogle Scholar
  11. Druker B.J. (2002). Perspectives on the development of a molecularly targeted agent. Cancer Cell 1, 31–36.CrossRefGoogle Scholar
  12. Druker, B. J., Sawyers, C. L., Capdeville, R., Ford, J. M., Baccarani, M, and Goldman, J. M. (2001a). Chronic myelogenous leukemia. Hematology (Am Soc Hematol Educ Program), 87–112.Google Scholar
  13. Druker, B. J., Sawyers, C. L., Kantarjian, H., Resta, D. J., Reese, S. F., Ford, J. M., Capdeville, R., and Talpaz, M. (2001b). Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344, 1038–10Google Scholar
  14. Druker.
    B. J., Tamura, S., Buchdunger, E., Ohno, S., Segal, G. M., Fanning, S., Zimmermann, J., and Lydon, N. B. (1996). Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 2, 561–566.CrossRefGoogle Scholar
  15. Faderl.
    S., Talpaz, M, Estrov, Z., O’Brien, S., Kurzrock, R., and Kantarjian, H. M. (1999). The biology of chronic myeloid leukemia. N Engl J Med 341, 164–172.CrossRefGoogle Scholar
  16. Gazit.
    A., Yee, K., Uecker, A., Bohmer, F. D., Sjoblom, T., Ostman, A., Waltenberger, J., Golomb, G., Banai, S., Heinrich, M. C, and Levitzki, A. (2003). Tricyclic quinoxalines as potent kinase inhibitors of PDGFR kinase, Flt3 and Kit. Bioorg Med Chem 11, 2007–2018.CrossRefGoogle Scholar
  17. Goldman.
    J. M, and Druker, B. J. (2001). Chronic myeloid leukemia: current treatment options. Blood 98, 2039–2042.CrossRefGoogle Scholar
  18. Gorre.
    M. E., Mohammed, M., Ellwood, K., Hsu, N., Paquette, R., Rao, P. N., and Sawyers, C. L. (2001). Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293, 876–880.CrossRefGoogle Scholar
  19. Heinrich.
    M. C, Blanke, C. D., Druker, B. J., and Corless, C. L. (2002a). Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol 20, 1692–1703.CrossRefGoogle Scholar
  20. Heinrich.
    M. C, Griffith, D. J., Druker, B. J., Wait, C. L., Ott, K. A., and Zigler, A. J. (2000). Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 96, 925–932.Google Scholar
  21. Heinrich.
    M. C, Rubin, B. P., Longley, B. J., and Fletcher, J. A. (2002b). Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations. Hum Pathol 33, 484–495.CrossRefGoogle Scholar
  22. Hofmann.
    W. K., de Vos, S., Elashoff, D., Gschaidmeier, H., Hoelzer, D., Koeffler, H. P., and Ottmann, O. G. (2002). Relation between resistance of Philadelphia-chromosome-positive acute lymphoblastic leukaemia to the tyrosine kinase inhibitor STI571 and gene-expression profiles: a gene-expression study. Lancet 359, 481–486.Google Scholar
  23. Kantarjian.
    H., Sawyers, C, Hochhaus, A., Guilhot, F., Schiffer, C, Gambacorti-Passerini, C, Niederwieser, D., Resta, D., Capdeville, R., Zoellner, U., et al. (2002). Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 346, 645–652.CrossRefGoogle Scholar
  24. Kovalenko.
    M., Gazit, A., Bohmer, A., Rorsman, C, Ronnstrand, L., Heldin, C. H., Waltenberger, J., Böhmer, F. D., and Levitzki, A. (1994). Selective platelet-derived growth factor receptor kinase blockers reverse sistransformation. Cancer Res 54, 6106–6114.Google Scholar
  25. Levitzki.
    A. (1994). Signal-transduction therapy. A novel approach to disease management. Eur J Biochem 226, 1–13.Google Scholar
  26. Levitzki.
    A. (1999). Protein tyrosine kinase inhibitors as novel therapeutic agents. Pharmacol Ther 82, 231–239.Google Scholar
  27. Levitzki.
    A. (2003). Protein kinase inhibitors as a therapeutic modality. Acc Chem Res 36, 462–469.Google Scholar
  28. Levitzki, A., and Gazit, A. (1995). Tyrosine kinase inhibition: an approach to drug development. Science 267, 1782-1788.Google Scholar
  29. 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.CrossRefGoogle Scholar
  30. Marx.
    J. (2001). Cancer research. Why some leukemia cells resist STI-571. Science 292, 2231–2233.Google Scholar
  31. Meydan.
    N., Grunberger, T., Dadi, H., Shahar, M., Arpaia, E., Lapidot, Z., Leeder, J. S., Freedman, M., Cohen, A., Gazit, A.,. et al. (1996). Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature 379, 645–648.Google Scholar
  32. Nagane.
    M., Levitzki, A., Gazit, A., Cavenee, W. K., and Huang, H. J. (1998). Drug resistance of human glioblastoma cells conferred by a tumor-specific mutant epidermal growth factor receptor through modulation of Bcl-XL and caspase-3-like proteases. Proc Natl Acad Sei USA 95, 5724–5729.CrossRefGoogle Scholar
  33. Nagane, M., Narita, Y., Mishima, K., Levitzki, A., Burgess, A. W., Cavenee, W. K., and Huang, H. J. (2001). Human glioblastoma xenografts overexpressing a tumor-specific mutant epidermal growth factor receptor sensitized to cisplatin by the AG1478 tyrosine kinase inhibitor. JNeurosurg 95, 472479.Google Scholar
  34. O’Leary, T., and Berman, J. J. (2002). Gastrointestinal stromal tumors: answers and questions. Hum Pathol 33, 456-458.Google Scholar
  35. Osherov.
    N., Gazit, A., Gilon, C, and Levitzki, A. (1993). Selective inhibition of the epidermal growth factor and HER2/neu receptors by tyrphostins. J Biol Chem 268, 11134–11142.Google Scholar
  36. Palumbo.
    G. A., Yarom, N., Gazit, A., Sandalon, Z., Baniyash, M., Kleinberger-Doron, N., Levitzki, A., and Ben-Yehuda, D. (1997). The tryphostin AG 17 induces apoptosis and inhibition of cdk2 activity in a lymphoma cell line that overexpresses bcl-2. Cancer Res 57, 2434–2439.Google Scholar
  37. Roumiantsev.
    S., Shah, N. P., Gorre, M. E, Nicoll, J., Brasher, B. B., Sawyers, C. L., and Van Etten, R. A. (2002). Clinical resistance to the kinase inhibitor STI-571 in chronic myeloid leukemia by mutation of Tyr-253 in the Abl kinase domain P-loop. Proc Natl Acad Sei USA 99, 10700–10705.CrossRefGoogle Scholar
  38. Schindler.
    T., Sicheri, F., Pico, A., Gazit, A., Levitzki, A., and Kuriyan, J. (1999). Crystal structure of Hck in complex with a Src family-selective tyrosine kinase inhibitor. Mol Cell 3, 639–648.CrossRefGoogle Scholar
  39. Tsai.
    C. M., Levitzki, A., Wu, L. H., Chang, K. T., Cheng, C. C, Gazit, A., and Perng, R. P. (1996). Enhancement of chemosensitivity by tyrphostin AG825 in high-pl85(neu) expressing non-small cell lung cancer cells. Cancer /tes 56, 1068–1074. von Bubnoff, N., Schneller, F., Peschel, C, and Duyster, J. (2002). BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study. Lancet 359, 487-491.Google Scholar
  40. Wakeling.
    A. E., Guy, S. P., Woodburn, J. R., Ashton, S. E., Curry, B. J., Barker, A. J., and Gibson, K. H. (2002). ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res 62, 5749–5754.Google Scholar
  41. Wisniewski.
    D., Lambek, C. L., Liu, C, Strife, A., Veach, D. R., Nagar, B., Young, M. A., Schindler, T., Bornmann, W. G., Bertino, J. R.,. et al (2002). Characterization of potent inhibitors of the Bcr-Abl and the c-kit receptor tyrosine kinases. Cancer Res 62, 4244–4255.Google Scholar
  42. Zhu, X., Kim, J. L., Newcomb, J. R., Rose, P. E., Stover, D. R., Toledo, L. M., Zhao, H., and Morgenstern, K. A. (1999). Protein, Structure Structural analysis of the lymphocyte-specific kinase Lck in complex with non-selective and Src family selective kinase inhibitors. Structure Fold Des 7, 651–661.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2003

Authors and Affiliations

  • Alexander Levitzki
    • 1
  • Dina Ben-Yehudah
    • 2
  1. 1.Unit of Cellular Signaling, Department of Biological Chemistry, The Alexander Silberman Institute of Life SciencesThe Hebrew University of JerusalemJerusalemIsrael
  2. 2.Department of HematologyHadassah University HospitalJerusalemIsrael

Personalised recommendations