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CHRONIC MYELOGENOUS LEUKEMIA

In vitro evidence of synergistic efficacy with asciminib combined with reduced dose of ATP-binding pocket tyrosine kinase inhibitors according to the ABL1 kinase domain mutation profile

Leukemia volume 38, pages 412–415 (2024)Cite this article

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The advent of tyrosine kinase inhibitors targeting the ATP binding pocket within the BCR-ABL1 protein has revolutionized CML treatment, and the survival of patients diagnosed in chronic phase is approaching that of age-matched control population [1, 2]. ABL1 kinase domain mutations (KDMs) disrupt TKI binding, causing clinical resistance and variable effects on efficacy of ATP-binding pocket inhibitors. [3].

Recently, asciminib (ASC), a “specifically targeting the ABL1 myristoyl pocket inhibitor” or STAMP inhibitor, has been incorporated into the CML therapeutic algorithm. ASC functions as an allosteric inhibitor, binding to the myristoyl pocket within the C-lobe of the ABL1 protein, in contrast to 1st–3rd generation TKIs that target the ATP-binding pocket [4,5,6]. This binding action causes the SH2 and SH3 domains to interact in such a way that renders ABL1 catalytically inactive [4, 5, 7].

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Fig. 1: The combination of ASC and ABPI, with the baseline inhibitory concentration reduced by half, demonstrates enhanced inhibition compared to the baseline inhibitory concentration of ABPI alone.
Fig. 2: Combination Treatment Strategy of Each ABPI and ASC in Various ABL1-KDM.

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Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT)(Nos. 1711180477, 2022R1A2C2091571). Additionally, this work was supported by Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare (HN21C0954, Republic of Korea) and was supported by the Princess Margaret Cancer Foundation in part. We also appreciate Dr. Igor Novitzky-Basso for his critical review of the manuscript.

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Authors and Affiliations

  1. Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Republic of Korea

    Ho-Jae Han & Jong-Won Kim

  2. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

    Jaeyoon John Kim, Danielle Pyne, Anthea Travas, Amirthagowri Ambalavanan & Dennis Dong Hwan Kim

  3. Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan

    Shinya Kimura

  4. Deininger Lab, Versiti Blood Research Institute, Milwaukee, WI, USA

    Michael W. Deininger

  5. Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

    Jong-Won Kim

  6. Department of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada

    Dennis Dong Hwan Kim

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Contributions

HJH, DDHK, and JWK designed the study. Data analyses and interpretation were conducted by DDHK, HJH, and JWKSK. and MWD provided the murine cell line and offered technical advice. HJH conducted all experiments, and DDHK, HJH, and MWD collaborated on writing the manuscript. HJH, JJK, DP, AT, AA, SK, MWD, JWK, and DDHK. critically reviewed the manuscript and approved the final version.

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Correspondence to Jong-Won Kim or Dennis Dong Hwan Kim.

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Han, HJ., Kim, J.J., Pyne, D. et al. In vitro evidence of synergistic efficacy with asciminib combined with reduced dose of ATP-binding pocket tyrosine kinase inhibitors according to the ABL1 kinase domain mutation profile. Leukemia 38, 412–415 (2024). https://doi.org/10.1038/s41375-023-02122-5

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