Strategies to overcome resistance to targeted protein kinase inhibitors

Nat Rev Drug Discov. 2004 Dec;3(12):1001-10. doi: 10.1038/nrd1579.


Selective inhibition of protein tyrosine kinases is gaining importance as an effective therapeutic approach for the treatment of a wide range of human cancers. However, as extensively documented for the BCR-ABL oncogene in imatinib-treated leukaemia patients, clinical resistance caused by mutations in the targeted oncogene has been observed. Here, we look at how structural and mechanistic insights from imatinib-insensitive Bcr-Abl have been exploited to identify second-generation drugs that override acquired target resistance. These insights have created a rationale for the development of either multi-targeted protein kinase inhibitors or cocktails of selective antagonists as antitumour drugs that combine increased therapeutic potency with a reduced risk of the emergence of molecular resistance.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / chemistry
  • Drug Delivery Systems / methods*
  • Drug Resistance / drug effects
  • Drug Resistance / genetics
  • Drug Resistance / physiology*
  • Humans
  • Molecular Sequence Data
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / chemistry


  • Antineoplastic Agents
  • Protein Kinase Inhibitors