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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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 (email@example.com). 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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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.
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