Skip to main content
SpringerLink
Log in

Kinase inhibitors translate lab discoveries into exciting new cures for cancers

  • Basic Science for Clinicians
  • Published:
The Indian Journal of Pediatrics Aims and scope Submit manuscript

Abstract

Genetic mutations can lead to abnormal activation of certain kinases that in turn lead to excessive cell division seen in cancers. Inhibitors of over activated kinases can theoretically inhibit cancer causing pathways and result in tumor shrinkage. These discoveries have sparked a revolution in drug discovery with many small molecule kinases inhibitors now being used in cancer clinical trials. The amazing success of Imatinib, a blocker of the bcr-abl kinase in chronic myeloid leukemia has shown that the drugs based on these strategies can improve cure rates in cancer. In this article, the authors review the concepts of kinase inhibition in cancer and principles behind the success of imitanib. The authors also review other promising kinase inhibitors being used in clinical trials that are expected to aid the fight against cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Goldman JM. Therapeutic strategies for chronic myeloid leukemia in the chronic (stable) phase.Semin Hematol 2003; 40: 10.

    PubMed  Google Scholar 

  2. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning Set al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth ofbcr-abl positive cells.Nat Med 1996; 2: 561.

    Article  PubMed  CAS  Google Scholar 

  3. Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini Cet al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia.N Engl J Med 2002; 346: 645.

    Article  PubMed  CAS  Google Scholar 

  4. O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes Fet al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia.N Engl J Med 2003; 348: 994.

    Article  PubMed  CAS  Google Scholar 

  5. Sawyers CL, Hochhaus A, Feldman E, Goldman JM, Miller CB, Ottmann OGet al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study.Blood 2002; 99: 3530.

    Article  PubMed  CAS  Google Scholar 

  6. Talpaz M, Silver RT, Druker BJ, Goldman JM, Gambacorti-Passerini C, Guilhot Fet al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase II study.Blood 2002:99 : 1928.

    Article  PubMed  CAS  Google Scholar 

  7. Weisberg E, Griffin JD. Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines.Blood 2000; 95: 3498.

    PubMed  CAS  Google Scholar 

  8. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Na Rao PNet al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification.Science 2001; 293: 876.

    Article  PubMed  CAS  Google Scholar 

  9. Donato NJ, Wu JY, Stapley J, Gallick G, Lin H, Arlinghaus Ret al. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia dells selected for resistance to STI571.Blood 2003; 101: 690.

    Article  PubMed  CAS  Google Scholar 

  10. Gambacorti-Passerini CB, Gunby RH, Piazza R, Galietta A, Rostagno R, Scapozza L. Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias.Lancet Oncol 2003; 4: 75.

    Article  PubMed  Google Scholar 

  11. Blagosklonny MV. STI-571 must select for drug-resistant cells but ’no cell breathes fire out of its nostrils like a dragon’.Leukemia 2002; 16: 570.

    Article  PubMed  CAS  Google Scholar 

  12. Nagar B, Bornmann WG, Pellicena P, Schindler T, Veach DR, Miller WTet al. Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571).Cancer Res 2002; 62: 4236.

    PubMed  CAS  Google Scholar 

  13. Demetri GD. Targeting c-kit mutations in solid tumors: scientific rationale and novel therapeutic options.Semin Oncol 2001; 28: 19.

    Article  PubMed  CAS  Google Scholar 

  14. Demetri GD, vonMehren M, Blanke CD, Van denAbbeele AD, Eisenberg Bet al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors.N Engl J Med 2002; 347: 472.

    Article  PubMed  CAS  Google Scholar 

  15. Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes Jet al A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome.N Engl J Med 2003; 348: 1201.

    Article  PubMed  CAS  Google Scholar 

  16. Apperley JF, Gardembas M, Melo JV, Russell-Jones R, Bain BJ, Baxter EJet al. Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta.N Engl J Med 2002; 347: 481.

    Article  PubMed  CAS  Google Scholar 

  17. Shawver LK, Slamon D, Ullrich A. Smart drugs: tyrosine kinase inhibitors in cancer therapy.Cancer Cell 2002; 1: 117.

    Article  PubMed  CAS  Google Scholar 

  18. Grunwald V, Hidalgo M. Developing inhibitors of the epidermal growth factor receptor for cancer treatment.J Natl Cancer Inst 2003; 95: 851.

    PubMed  Google Scholar 

  19. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde Aet al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.N Engl J Med 2001; 344: 783.

    Article  PubMed  CAS  Google Scholar 

  20. Kelly K, Averbuch S. Gefitinib: phase II and III results in advanced non-small cell lung cancer.Semin Oncol 2004; 31: 93.

    Article  PubMed  CAS  Google Scholar 

  21. Giaccone G, Herbst RS, Manegold C, Scagliotri G, Rosell R, Miller Vet al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 1.J Clin Oncol 2004; 22: 777.

    Article  PubMed  CAS  Google Scholar 

  22. Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold Cet al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 2.J Clin Oncol 2004; 22: 785.

    Article  PubMed  CAS  Google Scholar 

  23. Hidalgo M, Siu LL, Nemunaitis J, Rizzo J, Hammond LA, Takimoto Cet al. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies.JClin Oncol 2001; 19: 3267.

    CAS  Google Scholar 

  24. Ciardiello F, De Vita F, Orditura M, De Placido S, Tortora G. Epidermal growth factor receptor tyrosine kinase inhibitors in late stage clinical trials.Expert Opin Emerg Drugs 2003; 8: 501.

    Article  PubMed  CAS  Google Scholar 

  25. Folkman J. Angiogenesis inhibitors: a new class of drugs.Cancer Biol Ther 2003; 2: S127.

    PubMed  CAS  Google Scholar 

  26. Garber K. Research retreat: Pfizer eliminates Sugen, shrinks cancer infrastructure.J Natl Cancer lnst 2003; 95: 1036.

    Article  Google Scholar 

  27. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SLet al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer.NEngl J Med 2003; 349: 427.

    Article  CAS  Google Scholar 

  28. Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia.Blood 2002; 100: 1532.

    Article  PubMed  CAS  Google Scholar 

  29. Levis M, Allebach J, Tse KF, Zheng R, Baldwin BR, Smith BDet al. A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cellsin vitro and in vivo.Blood 2002; 99: 3885.

    Article  PubMed  CAS  Google Scholar 

  30. Propper DJ, McDonald AC, Man A, Thavasu P, Balkwill F, Braybrooke JPet al. Phase I and pharmacokinetic study of PKC412, an inhibitor of protein kinase C.J Clin Oncol 2001; 19: 1485.

    PubMed  CAS  Google Scholar 

  31. O’Farrell AM, Abrams TJ, Yuen HA, Ngai TJ, Louie SGet al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activityin vitro and in vivo.Blood 2003; 101: 3597.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Amit Verma

  2. Strategic Analysis Healthcare Inc, Dallas, Texas, USA

    Mani Mohindru & Amit Verma

Authors
  1. Mani Mohindru
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amit Verma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amit Verma.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mohindru, M., Verma, A. Kinase inhibitors translate lab discoveries into exciting new cures for cancers. Indian J Pediatr 71, 713–718 (2004). https://doi.org/10.1007/BF02730661

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02730661

Key words

Search

Navigation