Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL - PubMed (original) (raw)

Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL

Mohammad Azam et al. Cell. 2003.

Free article

Abstract

The Bcr-Abl fusion protein kinase causes chronic myeloid leukemia and is targeted by the signal transduction inhibitor STI-571/Gleevec/imatinib (STI-571). Sequencing of the BCR-ABL gene in patients who have relapsed after STI-571 chemotherapy has revealed a limited set of kinase domain mutations that mediate drug resistance. To obtain a more comprehensive survey of the amino acid substitutions that confer STI-571 resistance, we performed an in vitro screen of randomly mutagenized BCR-ABL and recovered all of the major mutations previously identified in patients and numerous others that illuminate novel mechanisms of acquired drug resistance. Structural modeling implies that a novel class of variants acts allosterically to destabilize the autoinhibited conformation of the ABL kinase to which STI-571 preferentially binds. This screening strategy is a paradigm applicable to a growing list of target-directed anti-cancer agents and provides a means of anticipating the drug-resistant amino acid substitutions that are likely to be clinically problematic.

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Comment in

• Variation on an Src-like theme.
  Harrison SC. Harrison SC. Cell. 2003 Mar 21;112(6):737-40. doi: 10.1016/s0092-8674(03)00196-x. Cell. 2003. PMID: 12654240 Review.

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