Mechanisms of resistance to BCR-ABL TKIs and the therapeutic strategies: A review

Crit Rev Oncol Hematol. 2015 Mar;93(3):277-92. doi: 10.1016/j.critrevonc.2014.11.001. Epub 2014 Nov 13.

Abstract

BCR-ABL caused by the translocation of t(9,22) with elevated tyrosine-kinase activity could induce leukemia in mice, which established BCR-ABL as the molecular pathogenic event in CML (Chronic myeloid leukemia). In recent years, a variety of tyrosine kinase inhibitors (TKIs) targeting at BCR-ABL specifically and effectively have been developed, which has fundamentally promoted the treatment of CML. However, the efficacy of TKIs was limited by its resistance induced by the development of kinase domain mutations and other mechanisms illustrated. In this review, we summarized BCR-ABL inhibitors approved by Food and Drug Administration (FAD), with the same concerns focus on the resistant mechanisms of BCR-ABL inhibitors and therapeutic resistant strategies.

Keywords: Anticancer drug; BCR–ABL; Resistance; Therapeutic stategies; Tyrosine kinase inhibitors.

Publication types

  • Review

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Drug Resistance, Neoplasm* / genetics
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism
  • Gene Expression Regulation, Leukemic
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
  • Mutation
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Signal Transduction / drug effects
  • Tumor Microenvironment

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Fusion Proteins, bcr-abl