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TP-0903 is active in models of drug-resistant acute myeloid leukemia
Jae Yoon Jeon, … , Bhavana Bhatnagar, Sharyn D. Baker
Jae Yoon Jeon, … , Bhavana Bhatnagar, Sharyn D. Baker
Published December 3, 2020
Citation Information: JCI Insight. 2020;5(23):e140169. https://doi.org/10.1172/jci.insight.140169.
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Research Article Hematology Oncology

TP-0903 is active in models of drug-resistant acute myeloid leukemia

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Abstract

Effective treatment for AML is challenging due to the presence of clonal heterogeneity and the evolution of polyclonal drug resistance. Here, we report that TP-0903 has potent activity against protein kinases related to STAT, AKT, and ERK signaling, as well as cell cycle regulators in biochemical and cellular assays. In vitro and in vivo, TP-0903 was active in multiple models of drug-resistant FLT3 mutant AML, including those involving the F691L gatekeeper mutation and bone marrow microenvironment–mediated factors. Furthermore, TP-0903 demonstrated preclinical activity in AML models with FLT3-ITD and common co-occurring mutations in IDH2 and NRAS genes. We also showed that TP-0903 had ex vivo activity in primary AML cells with recurrent mutations including MLL-PTD, ASXL1, SRSF2, and WT1, which are associated with poor prognosis or promote clinical resistance to AML-directed therapies. Our preclinical studies demonstrate that TP-0903 is a multikinase inhibitor with potent activity against multiple drug-resistant models of AML that will have an immediate clinical impact in a heterogeneous disease like AML.

Authors

Jae Yoon Jeon, Daelynn R. Buelow, Dominique A. Garrison, Mingshan Niu, Eric D. Eisenmann, Kevin M. Huang, Megan E. Zavorka Thomas, Robert H. Weber, Clifford J. Whatcott, Steve L. Warner, Shelley J. Orwick, Bridget Carmichael, Emily Stahl, Lindsey T. Brinton, Rosa Lapalombella, James S. Blachly, Erin Hertlein, John C. Byrd, Bhavana Bhatnagar, Sharyn D. Baker

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Figure 5

TP-0903 is active in models of AML with recurrent mutations.

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TP-0903 is active in models of AML with recurrent mutations.
(A) Inhibit...
(A) Inhibition of cell viability (CellTiterGlo assay, 72 hours, n = 4) (left panel) and colony formation (7 day CFU assay, n = 4) of primary FLT3-ITD/MLL-PTD murine leukemia cells treated ex vivo with indicated TKI. (B) Morphology of treated cells at day 7 by Wright Giemsa staining. Total magnification, 400×. (C) Inhibition of cell viability (CellTiterGlo assay, 72 hours, n = 3–6) and colony formation (7 day CFU assay, n = 4) of primary FLT3-ITD/IDH2-R140Q murine leukemia cells treated ex vivo with indicated TKI. (D) Survival by Kaplan-Meier analysis (left panel) and spleen weight at end of study (right panel) following treatment with TP-0903 (40 mg/kg) once daily or vehicle (n = 5/cohort). Black bars depict days of treatment. (E) Inhibition of viability of human primary AML samples with FLT3-ITD and indicated co-occurring mutations treated with indicated TKI ex vivo (CellTiterGlo assay, 72 hours, n = 3). (F) Inhibition of colony formation of FLT3-ITD+ human primary AML samples treated with indicated TKI (14 day CFU assay, n = 2). P values were determined using either unpaired 2-tailed Student’s t test or log rank test. Specific P values are indicated within the figure.
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