Molecular mechanisms of drug resistance in tyrosine kinases cAbl and cKit

Crit Rev Biochem Mol Biol. 2011 Aug;46(4):295-309. doi: 10.3109/10409238.2011.578612. Epub 2011 May 4.

Abstract

The inhibition of protein kinases has gained general acceptance as an effective approach to treat a wide range of cancers. However, in many cases, prolonged administration of kinase inhibitors often leads to acquired resistance, and the therapeutic effect is subsequently diminished. The wealth of recent studies using biochemical, kinetic, and structural approaches have revealed the molecular basis for the clinically observed resistance. In this review, we highlight several of the most common molecular mechanisms that lead to acquired resistance to kinase inhibitors observed with the cAbl (cellular form of the Abelson leukemia virus tyrosine kinase) and the type III receptor tyrosine kinase cKit, including a newly identified mechanism resulting from accelerated kinase activation caused by mutations in the activation loop. Strategies to overcome the loss of drug sensitivity that represents a challenge currently facing the field and the emerging approaches to circumvent resistance are discussed.

Publication types

  • Review

MeSH terms

  • Benzamides
  • Binding Sites
  • Drug Resistance, Neoplasm*
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Fusion Proteins, bcr-abl / chemistry
  • Humans
  • Hydrogen Bonding
  • Imatinib Mesylate
  • Indoles / pharmacology
  • Mutation
  • Phosphorylation
  • Piperazines / pharmacology
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Stability
  • Protein Structure, Tertiary
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / chemistry
  • Proto-Oncogene Proteins c-kit / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-kit / chemistry
  • Pyrimidines / pharmacology
  • Pyrroles / pharmacology
  • Signal Transduction
  • Sunitinib

Substances

  • Benzamides
  • Indoles
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Pyrroles
  • Imatinib Mesylate
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-kit
  • Fusion Proteins, bcr-abl
  • Sunitinib