Is there a cloud in the silver lining for imatinib?

Abstract

Imatinib mesylate (Gleevec) or Glivec), a small molecule tyrosine kinase inhibitor for the treatment of chronic myeloid leukaemia, has been said to herald the dawn of a new era of rationally designed, molecularly targeted oncotherapy. Lurking on the same new horizon, however, is the age-old spectre of drug resistance. This review sets the intoxicating clinical perspective against the more sobering laboratory evidence of such divergent mechanisms of imatinib resistance as gene amplification and stem cell quiescence. Polychemotherapy has already been considered to combat resistance, but a more innovative, as yet unformulated, approach may be advocated.

Figure 1

(A) Molecular structure of imatinib. (B) Mode of action of imatinib. (i) ATP binds to BCR/ABL and phosphorylates a tyrosine (Y) residue of the substrate. The substrate can then bind to an effector molecule triggering the cellular response. (ii) Imatinib binds to BCR/ABL blocking the binding of ATP, thus the substrate tyrosine molecule is not phosphorylated and cannot in turn bind and activate the effector molecule.