Mechanisms of Resistance

Resistance to BCR-ABL tyrosine kinase inhibitors (TKIs)

Several different mechanisms are thought to be responsible for the development of resistance to BCR-ABL TKIs. These potential mechanisms are based on studies of resistant cell lines developed in the laboratory and cells from patients with resistant disease. Although substantial progress has been made in describing the mechanisms for resistance, the underlying causes have yet to be understood. Moreover, resistance to a particular drug is likely to be multifactorial. ⁴

Potential mechanisms of resistance to BCR-ABL tyrosine kinase inhibitors include:

• BCR-ABL kinase mutations—the most common mechanism of resistance^4,9
  • The frequency of mutations is 40%-90% of resistant patients, depending on method of detection, definition of resistance, and CML phase (increased in advanced phases)
  • Mutations in regions of the BCR-ABL kinase domain confer higher degrees of imatinib resistance, including the ATP binding or P-loop, the activation loop, and others
  • Mutations conferring resistance prevent imatinib from binding to BCR-ABL
• BCR-ABL overexpression^4,10
  • Amplification of BCR-ABL gene leads to resistance in some patients
• Multidrug resistance gene overexpression^4,11
  • Increased production of transmembrane efflux pump that transports drug from target cells
• Additional oncogenic pathways^9,12
  • Activations of signaling pathways downstream from BCR-ABL would function independently of BCR-ABL
  • SRC family of kinases (LYN, HCK) increased activity by gene overexpression

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