Mechanisms of primary and secondary resistance to imatinib in chronic myeloid leukemia

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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
12:40

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

Alfonso Quintás-Cardama1, Hagop M Kantarjian, Jorge E Cortes

  • 1Department of Leukemia at The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. aquintas@mdanderson.org

Cancer Control : Journal of the Moffitt Cancer Center
|April 2, 2009
PubMed
Abstract

Insights

Resistance to imatinib, a tyrosine kinase inhibitor (TKI) for chronic myeloid leukemia (CML), can occur due to BCR-ABL1 mutations or other factors. New TKI agents are in development to overcome this resistance.

Area of Science:

  • Oncology
  • Hematology
  • Pharmacology

Background:

  • Chronic myeloid leukemia (CML) is often treated with tyrosine kinase inhibitors (TKIs) like imatinib mesylate.
  • While most CML patients respond to imatinib, some develop resistance, either initially or during therapy.

Purpose of the Study:

  • To review the known mechanisms of primary and secondary resistance to imatinib and other TKIs in CML management.
  • To provide an overview of the current understanding of TKI resistance in CML.

Main Methods:

  • Literature review of mechanisms of resistance to imatinib and other TKIs in CML.
  • Analysis of identified resistance pathways including genetic mutations and pharmacokinetic factors.

Main Results:

  • BCR-ABL1 kinase domain mutations are responsible for 30-40% of imatinib resistance cases.
  • Other resistance mechanisms include BCR-ABL1 amplification, SRC family kinase overexpression, and pharmacokinetic/pharmacodynamic issues.

Conclusions:

  • Several novel therapeutic agents targeting known resistance mechanisms are under development and entering clinical trials.
  • Further research is needed to fully elucidate all resistance mechanisms in CML.

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