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Anticipating Clinical Resistance to Target-Directed Agents

The BCR-ABL Paradigm

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Abstract

The deregulated tyrosine kinase activity of BCR-ABL is necessary and sufficient to induce chronic myelogenous leukemia (CML). This observation has paved the way for the development of small-molecule inhibitors specifically targeting the kinase activity of the BCR-ABL protein. Indeed, the amazing success of imatinib has revolutionized the whole area of targeted cancer therapeutics. However, enthusiasm for the striking efficacy of imatinib has been tempered by the development of clinical resistance. In essentially all cases, resistance results from kinase domain mutations and/or overexpression of the BCR-ABL gene. To overcome resistance, several novel BCR-ABL inhibitors have been developed and are in clinical trials, though it is inevitable that resistance to second-generation inhibitors will occur as well. Nonetheless, kinases represent an attractive target for therapeutic intervention in several diseases and, at present, some 50 different kinase inhibitors are in clinical trials. We anticipate that resistance to these compounds will follow mechanisms similar to those observed with imatinib. Resistance mutations cause their effect either by direct steric hindrance to drug binding or by allosterically modulating kinase dynamics. This review highlights the principal mechanisms underlying point mutations from these two different classes to confer drug resistance.

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Acknowledgments

The authors wish to thank members of the Daley lab for critical review and revision of the manuscript, especially Drs Shannon M. Freeman, William M. Lensch, and Frank Yates.

Research was supported by grants from the National Institutes of Health (NIH), the NIH Director’s Pioneer Award of the NIH Roadmap for Medical Research, and by the Thomas Anthony Pappas Charitable Foundation. GQD is a recipient of the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research.

The authors have no conflicts of interest that are directly relevant to the content of this review.

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  1. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA

    Mohammad Azam &  George Q. Daley

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  1. Mohammad Azam
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  2. George Q. Daley
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Correspondence to George Q. Daley.

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Azam, M., Daley, G.Q. Anticipating Clinical Resistance to Target-Directed Agents. Mol Diag Ther 10, 67–76 (2006). https://doi.org/10.1007/BF03256446

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