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Clinical Use of Tyrosine Kinase Inhibitors: Therapy for Chronic Myelogenous Leukemia and Other Cancers

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Clinical Use of Tyrosine Kinase Inhibitors: Therapy for Chronic Myelogenous Leukemia and Other Cancers Vol. 6, 2965–2966, August 2000 Clinical Cancer Research 2965 Editorial Clinical Use of Tyrosine Kinase Inhibitors: Therapy for Chronic Myelogenous Leukemia and Other Cancers Nicholas J. Donato1 and Moshe Talpaz derivative was characterized for its ability to inhibit v-abl, c-abl, Department of Bioimmunotherapy, University of Texas M. D. and bcr-abl tyrosine kinase activity through competitive ATP Anderson Cancer Center, Houston, Texas 77030 binding pocket interactions (14, 15). The compound STI571 emerged from these studies, and its in vitro and in vivo efficacy in inducing apoptosis or suppressing clonogenic leukemic cell Since the initial discovery of tyrosine-specific protein ki- growth suggested that it might be therapeutically useful for nases encoded by transforming viruses and their normal cellular treatment of CML (15–17). Whereas selective kinase inhibition homologues, there has been a great deal of interest in under- underlies its basic mechanism of action, the apoptotic response standing their role in cancer and exploring their potential as to STI571 in bcr-abl-positive cells is not completely understood. therapeutic targets. Several approaches confirmed the role of Transfer of total dependence of CML progenitors on bcr-abl tyrosine kinases in virtually every aspect of cellular transforma- signaling for their sustained growth or survival may be an tion including cell cycle progression, increased survival in re- important consideration in the clinical responsiveness to this sponse to apoptotic challenge, neovascularization, and aberrant drug. STI571 has been introduced into Phase I trials at three gene expression (for review, see Ref. 1). This information centers in the United States with very promising early results suggested that the diverse spectrum of tyrosine kinases and their (18). The drug is administered p.o., and biologically effective association with specific malignancies offered multiple targets levels are pharmacologically achievable. Preliminary clinical for chemotherapeutic intervention. However, exploitation of responses were noted in both the chronic and the more advanced these enzymes as specific tumor targets has only recently been stages of the disease. It is anticipated that STI571 will impact realized, and clinical application of tyrosine kinase-targeted the treatment of CML and may stimulate greater interest in the therapy is a new and growing field (2–4). clinical use of tyrosine kinase inhibitors. Initial discovery of small molecules that interfered with As suggested in earlier and more recent reports, STI571 ATP binding or utilization represented a major breakthrough in may be useful in other malignancies, including leukemias tyrosine kinase-targeted therapy (5). Subtle but measurable dis- characterized by expression of an alternate molecular form of tinctions in the ATP binding pocket of tyrosine kinases were bcr-abl (p190bcr-abl) and those expressing protein tyrosine exploitable, and specificity for individual kinases (or related kinases with ATP binding pockets structurally similar to enzymes) could be engineered into small molecules with char- c-abl (10, 14). Studies of STI571 activity on an available acteristics of conventional chemotherapeutic agents [molecular spectrum of tyrosine kinase targets suggested that c-kit and size, bioavailability, and cell and tissue uptake (5–8)]. The key platelet-derived growth factor receptor kinases are also in- to successful development of small molecular kinase inhibitors hibited by STI571, with affinities similar to those described has been in providing selective and potent inhibition of an for the bcr-abl family of kinases (14, 15). Therefore, patients oncogenic target. In some cancers, unregulated or aberrant ex- with tumors supported through activation or expression of pression of a single tyrosine kinase underlies transformation (9, one of these kinases may also benefit from STI571 therapy. 10), providing great opportunities for targeted therapy with In this regard, the report of c-kit expression in small cell lung tyrosine kinase inhibitors. cancer and its inhibition by STI571 published in this issue of CML2 is characterized in Ͼ95% of patients by the presence Clinical Cancer Research demonstrates the potential to treat of the Philadelphia chromosome, representing a reciprocal trans- seemingly unrelated cancers with a selective kinase inhibitor location of chromosomes 9 and 22 (11, 12). This translocation (19). Other tumors dependent on platelet-derived growth results in altered control of the c-abl tyrosine kinase and expres- factor receptor signaling (i.e., high-grade glioma) may also sion of a protein, termed bcr-abl, with exons derived from the be targets for STI571 therapy. c-abl gene and bcr locus (12). The resultant chimeric protein Development of kinase targeting inhibitors represents a expresses unregulated tyrosine kinase activity, and studies have monumental research effort that is beginning to shown good shown that its kinase activity is important in the etiology of clinical promise. Limited spectrum specificity and dependence CML and other diseases (13). Therefore, bcr-abl kinase inhibi- of tumors on an activated or unregulated protein kinase for an tion may have a direct impact on CML and other diseases. oncogenic contribution will continue to be most important con- After collection of the structural, enzymatic, and molecular siderations in the design, testing, and efficacy of these inhibi- characteristics of tyrosine kinases, a 2-phenylaminopyrimide tors. References Received 4/28/00; accepted 5/17/00. 1. Hunter, T. The Croonian Lecture, 1997. The phosphorylation of 1 To whom requests for reprints should be addressed, at University of proteins on tyrosine: its role in cell growth and disease. Philos. Trans. R. Texas M. D. Anderson Cancer Center, Box 303, 1515 Holcombe Bou- Soc. Lond. B Biol. Sci., 353: 583–605, 1998. levard, Houston, TX 77030. 2. Levitt, M. L., and Koty, P. P. Tyrosine kinase inhibitors in preclinical 2 The abbreviation used is: CML, chronic myelogenous leukemia. development. Investig. New Drugs, 17: 213–226, 1999. Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2000 American Association for Cancer Research. 2966 Clinical Use of Tyrosine Kinase Inhibitors 3. Levitzki, A. Protein tyrosine kinase inhibitors as novel therapeutic 12. Kurzrock, R., Gutterman, J. U., and Talpaz, M. The molecular agents. Pharmacol. Ther., 82: 231–239, 1999. genetics of Philadelphia chromosome-positive leukemias. N. Engl. 4. Klohs, W. D., Fry, D. W., and Kraker, A. J. Inhibitors of tyrosine J. Med, 319: 990–998, 1988. kinase. Curr. Opin. Oncol., 9: 562–568, 1997. 13. Daley, G. Q., Van Etten, R. A., and Baltimore, D. Induction of 5. Fry, D. W., Kraker, A. J., McMichael, A., Ambroso, L. A., Nelson, chronic myelogenous leukemia in mice by the P210bcr/abl gene of the J. M., Leopold, W. R., Connors, R. W., and Bridges, A. J. A specific Philadelphia chromosome. Science (Washington DC), 247: 824–830, inhibitor of the epidermal growth factor receptor tyrosine kinase. Sci- 1990. ence (Washington DC), 265: 1093–1095, 1994. 14. Buchdunger, E., Zimmermann, J., Mett, H., Meyer, T., Muller, M., 6. Traxler, P., and Furet, P. Strategies toward the design of novel and Regenass, U., and Lydon, N. B. Selective inhibition of the platelet- selective protein tyrosine kinase inhibitors. Pharmacol. Ther., 82: 195– derived growth factor signal transduction pathway by a protein-tyrosine 206, 1999. kinase inhibitor of the 2-phenylaminopyrimidine class. Proc. Natl. Acad. 7. Noble, M. E. M., and Endicott, J. A. Chemical inhibitors of cyclin- Sci. USA, 92: 2558–2562, 1995. dependent kinases: insights into design from X-ray crystallographic 15. Buchdunger, E., Zimmermann, J., Mett, H., Meyer, T., Muller, M., studies. Pharmacol. Ther., 82: 269–278, 1999. Druker, B. J., and Lydon, N. B. Inhibition of the Abl protein-tyrosine 8. Toledo, L. M., Lydon, N. B., and Elbaum, D. The structure-based kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. design of ATP-site directed protein kinase inhibitors. Curr. Med. Chem., Cancer Res, 56: 100–104, 1996. 6: 775–805, 1999. 16. le Coutre, P., Mologni, L., Cleris, L., Marchesi, E., Buchdunger, E., 9. Druker, B. J., Tamura, S., Buchdunger, E., Ohno, S., Segal, G. M., Giardini, R., Formelli, F., and Gambacorti-Passerini, C. In vivo eradi- Fanning, S., Zimmermann, J., and Lydon, N. B. Effects of a selective cation of human BCR/ABL-positive leukemia cells with an ABL kinase inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive inhibitor. J. Natl. Cancer Inst., 91: 163–168, 1999. cells. Nat. Med., 2: 561–566, 1996. 17. Deininger, M. W., Goldman, J. M., Lydon, N., and Melo, J. V. The 10. Beran, M., Cao, X., Estrov, Z., Jeha, S., Jin, G., O’Brien, S., Talpaz, tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of M., Arlinghaus R. B., Lydon, N. B., and Kantarjian, H. Selective inhibition of cell proliferation and BCR-ABL phosphorylation in acute BCR-ABL-positive cells. Blood, 90: 3691–3698, 1997. 18. Druker, B. J., Talpaz, M., Resta, D., Peng, B., Buchdunger, E., lymphoblastic leukemia cells expressing Mr 190,000 BCR-ABL protein by a tyrosine kinase inhibitor (CGP-57148). Clin. Cancer Res., 4: Ford, J., and Sawyer, C. Clinical efficacy and safety of an Abl specific 1661–1672, 1998. tyrosine kinase inhibitor as targeted therapy for chronic myelogenous 11. Ben-Neriah, Y., Daley, G. Q., Mes-Masson, A-M., Witte, O. N., leukemia. Blood, 94: 368a, 1999. and Baltimore,
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