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Target spectrum of the BCR-ABL tyrosine kinase inhibitors in chronic myeloid leukemia

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Abstract

BCR-ABL1 plays a key role in the pathogenesis of chronic myeloid leukemia (CML), and it has been investigated as a druggable target of tyrosine kinase inhibitors (TKIs) over two decades. Since imatinib, the first TKI for anti-cancer therapy, was successfully applied in CML therapy, further generation TKIs and a novel allosteric inhibitor targeting the myristate binding site have been developed as alternative options for CML management. However, significant concerns regarding toxicity profiles, especially in long-term treatment, have emerged from TKI clinical data. Efforts to reduce adverse events and serious complications are warranted not only for survival, but also quality of life in CML patients. A better understanding of the mechanism of action will help to identify on- and off-target effects of TKIs, and guide personalized TKI drug selection in each individual CML patient. Herein, this review summarizes the biologic mechanism of BCR-ABL1 inhibition and differential target spectra, and related off-target effects of each TKI.

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Authors and Affiliations

  1. Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada

    Hyewon Lee, Igor Novitzky Basso & Dennis Dong Hwan Kim

  2. Division of Tumor Immunology, Center for Hematologic Malignancies, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea

    Hyewon Lee

  3. Department of Hematology, Faculty of Medicine, University of Toronto, Toronto, Canada

    Dennis Dong Hwan Kim

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  1. Hyewon Lee
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DK has received honoraria and research grant from Novartis, Pfizer, and Paladin, has served on advisory boards for Novartis, Pfizer, and Paladin, and has received research grant from BMS. HL and INB have no conflicts of interests to declare.

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Lee, H., Basso, I.N. & Kim, D.D.H. Target spectrum of the BCR-ABL tyrosine kinase inhibitors in chronic myeloid leukemia. Int J Hematol 113, 632–641 (2021). https://doi.org/10.1007/s12185-021-03126-6

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