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Protein Kinases: Signatures in Cancer

  1. Janusz M Sowadski1,
  2. Robert K Suto2

Published Online: 15 DEC 2009

DOI: 10.1002/9780470015902.a0000659.pub2



How to Cite

Sowadski, J. M. and Suto, R. K. 2009. Protein Kinases: Signatures in Cancer. eLS. .

Author Information

  1. 1

    Advanced Kinase Diagnostics, Inc., Boston, Massachusetts, USA

  2. 2

    Xtal BioStructures, Inc., Natick, Massachusetts, USA

Publication History

  1. Published Online: 15 DEC 2009

This is not the most recent version of the article. View current version (16 FEB 2015)


Since the discovery of the first protein kinase crystal structure, structures of over 50 protein kinases have been solved. This crystallographic tour-de-force has catalysed structure-based design of specific inhibitors, resulting in over 100 000 patent protected molecules. One-third of the pharmaceutical industry R&D worldwide is directed towards kinase inhibition. Concerted efforts resulted in Food and Drug Administration approval for several drugs including the most successful oncology drug – imatinib (Gleevec) developed by Novartis. The challenge now is to overcome drug resistance and increase drug efficacy through genetic patient stratification in clinical trials and clinical practice. Clinical data of deoxyribonucleic acid (DNA) sequences that contain key genes serve as the basis for establishing signatures for responding patients and allow the ‘tailoring’ of a particular drug to specific patient populations. Such a signature-based approach can enhance the value of already approved drugs and may be used to treat patients with different cancer subtypes.

Key concepts:

  • All kinase inhibitors that are FDA approved as first in line oncology drugs compete with ATP binding to the kinase catalytic core.

  • Clinical responses of CML cancer patients to imatinib depend on the specific genetic signatures of the patients.

  • Resistance of CML patients to imatinib can be overcome by structure-based redesigning of the inhibitor molecule.

  • Imatinib can treat cancer patients with very different cancer subtypes, such as CML and GIST.

  • CML and GIST patients responding to imatinib have common activating kinase mutations.

  • Only 10% of NSCLC patients respond to gefitinib or erlotinib; these responding patients have specific genetic signatures.

  • Activating mutants of responding NSCLC patients have a lower affinity to ATP.

  • There is a common site in the catalytic core of kinases where mutations can lead to higher affinity to ATP and this site can also be associated with patients who develop resistance to imatinib, gefinitib and erlotinib.


  • kinase;
  • cancer;
  • drug design;
  • drug resistance;
  • Gleevec;
  • activating mutations