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BCR-ABL Mutations and Imatinib Resistance in Chronic Myeloid Leukemia Patients

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Genomics and Pharmacogenomics in Anticancer Drug Development and Clinical Response

Part of the book series: Cancer Drug Discovery and Development™ ((CDD&D))

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Summary

The discovery of a translocation between the Abelson oncogene (ABL1) on the long arm of chromosome 9 and the breakpoint cluster region (BCR) on chromosome 22 resulting in the BCR-ABL1 gene mutation was a landmark discovery in the pathogenesis of human leukemia. The decades of research into the structure and function of this aberrant gene culminated in development of imatinib mesylate, which has had an astounding benefit in the treatment of this disease. Despite its resounding success, a minority of patients developed resistance to imatinib. The unraveling of the multiple resistance mechanisms and the discovery of the dominant mechanism of point mutations in the ABL1 kinase portion of BCR-ABL1 has led to the development of second and subsequent generation agents that are active against these mutations. Dasatinib (Sprycel®) has rapidly achieved FDA approval for imatinib-resistant and intolerant CML. Nilotinib (Tasigna®) is undergoing FDA review. A host of other kinase inhibitors are in earlier stages of pre-clinical and clinical development. The structure–function relationships of imatinib in complex with BCR-ABL1 and the development of these new agents will certainly result in the use of combination therapy for CML and likely result in excellent long-term disease control and a probable cure. These developments have fueled the development of targeted therapy in multiple other malignancies and diseases and represent the beginnings of a golden age in the treatment of human disease.

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Acknowledgment

The author gratefully acknowledges Mrs. Denise Chase for transcription and development of this manuscript.

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  1. Division of Hematology Research, Mayo Clinic, Rochester, Minnesota, USA

    Mark R. Litzow MD

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  1. Mark R. Litzow MD
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  1. Department of Medicine, Section of Hematology/Oncology, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637-1470, USA

    Federico Innocenti

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Litzow, M.R. (2008). BCR-ABL Mutations and Imatinib Resistance in Chronic Myeloid Leukemia Patients. In: Innocenti, F. (eds) Genomics and Pharmacogenomics in Anticancer Drug Development and Clinical Response. Cancer Drug Discovery and Development™. Humana Press. https://doi.org/10.1007/978-1-60327-088-5_9

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