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ACUTE LYMPHOBLASTIC LEUKEMIA

Preclinical pharmacokinetic and pharmacodynamic evaluation of dasatinib and ponatinib for the treatment of T-cell acute lymphoblastic leukemia

Leukemia volume 37, pages 1194–1203 (2023)Cite this article

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Abstract

LCK is a novel therapeutic target in ~40% of T-cell acute lymphoblastic leukemia (T-ALL), and dasatinib and ponatinib can act as LCK inhibitors with therapeutic effects. We herein report a comprehensive preclinical pharmacokinetic and pharmacodynamic evaluation of dasatinib and ponatinib in LCK-activated T-ALL. In 51 human T-ALL cases, these two drugs showed similar patterns of cytotoxic activity, with ponatinib being slightly more potent. Given orally in mice, ponatinib was associated with slower clearance with a longer Tmax and higher AUC0-24 h, although maximum pLCK inhibition was comparable between the two drugs. After establishing the exposure-to-response models, we simulated the steady-state pLCK inhibitory effects of each drug at currently approved dosages in humans: dasatinib at 140 mg and ponatinib at 45 mg once daily are both sufficient to achieve >50% pLCK inhibition for 13.0 and 13.9 h/day, respectively, comparable to pharmacodynamic profiles of these agents in BCR::ABL1 leukemias. Moreover, we developed a dasatinib-resistant T-ALL cell line model with LCK T316I mutation, in which ponatinib retained partial activity against LCK. In conclusion, we described the pharmacokinetic and pharmacodynamic profiles of dasatinib and ponatinib as LCK inhibitors in T-ALL, providing critical data for the development of human trials of these agents.

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Fig. 1: Ponatinib shows antileukemic activity in LCK-activated T-ALL ex vivo and in vivo.
Fig. 2: PK and PD profiles of dasatinib and ponatinib in mice.
Fig. 3: Simulation of PK-PD after repetitive dasatinib and ponatinib dosing in human T-ALL.
Fig. 4: Dasatinib-resistant KOPT-K1 retains its sensitivity to ponatinib.

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Data availability

Whole genome sequencing data is deposited with the European Genome-Phenome Archive (accession number: EGAD00001006434). To request reagents included in this work, please contact JJY (jun.yang@stjude.org). Details of other experiments (e.g., ex vivo drug sensitivity assay for dasatinib, ponatinib and saracatinib, LC-MS for dasatinib and ponatinib) are provided in Supplementary Methods.

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Acknowledgements

We thank the Hartwell Center for Biotechnology, the Flow Cytometry and Cell Sorting Core, and the Animal Research Center at St. Jude Children’s Research Hospital for their technical assistance. We also thank all the patients and families for donating research specimens, as well as the clinicians and research staff for assistance in sample collection. This work was in part supported by the National Institutes of Health (P30CA21765, R01CA264837, and U01CA264610), American Lebanese Syrian Associated Charities, the Translational Research Program at the Leukemia & Lymphoma Society (6665-23), and the Takeda Pharmaceutical Company.

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Author notes

  1. Jianzhong Hu

    Present address: Amgen, 1 Amgen Center Drive, Thousand Oaks, CA, USA

  2. These authors contributed equally: Satoshi Yoshimura, John C. Panetta, Jianzhong Hu.

Authors and Affiliations

  1. Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Satoshi Yoshimura, John C. Panetta, Jianzhong Hu, Lie Li, Guoqing Du & Jun J. Yang

  2. Department of Advanced Pediatric Medicine, Tohoku University School of Medicine, Tokyo, Japan

    Satoshi Yoshimura & Akihiro Umezawa

  3. Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan

    Yoshihiro Gocho

  4. Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Seth E. Karol, Ching-Hon Pui & Jun J. Yang

  5. Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Charles G. Mullighan

  6. Department of Oncology and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA

    Marina Konopleva

  7. Department of Medicine Section of Hematology-Oncology, University of Chicago, Chicago, IL, USA

    Wendy Stock

  8. Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA

    David T. Teachey

  9. Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Nitin Jain

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Contributions

JJY initiated and led the project; JJY, JCP, SY, and JH designed the study and interpreted the results; SY, JH, and GD generated patient-derived xenografts (PDXs), performed experiments and ex vivo drug sensitivity tests; YG generated PDXs and performed ex vivo drug sensitivity tests when he was at St. Jude Children’s Research Hospital; LL measured plasma drug concentrations; JCP, SY, and JH performed data analyses; AU, C-HP, SEK, CGM, MK, WS, DTT, and NJ contributed reagents, materials and analyses tools; JJY, SY, and JCP wrote the manuscript; C-HP, SEK, CGM, MK, WS, DTT, and NJ provided relevant intellectual input and edited the manuscript; All the authors critically reviewed and commented on the manuscript.

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Correspondence to Jun J. Yang.

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Competing interests

This work was partly supported by Takeda Pharmaceutical Company. JH is a current employee of Amgen Inc.

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Yoshimura, S., Panetta, J.C., Hu, J. et al. Preclinical pharmacokinetic and pharmacodynamic evaluation of dasatinib and ponatinib for the treatment of T-cell acute lymphoblastic leukemia. Leukemia 37, 1194–1203 (2023). https://doi.org/10.1038/s41375-023-01900-5

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