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

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 6

TP-0903 is active in AML with RAS pathway mutations.

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TP-0903 is active in AML with RAS pathway mutations. (A) Dendogram of na...
(A) Dendogram of native kinase inhibition in OCI-AML3 cells treated with 100 nM TP-0903 for 2 hours in a KiNativ assay. All kinases detected are shown and grouped based on classification. Inhibition is relative to the DMSO control indicated on a spectrum of dark red (>90%), red (75%–90%), orange (50%–75%), yellow (35%–50%), and green (no change) bars. (B) Signaling inhibition of OCI-AML3 cells treated with DMSO or increasing concentrations of TP-0903 for 4 hours. Western blot analysis was performed on whole-cell lysates run on parallel gels with the indicated antibodies and is representative of 2 independent experiments. (C and D) Quantification of cell cycle phase (C) and mean (± SEM) annexin-V–positive cells (D) at the designated treatment times with TP-0903 (20 nM) or TP-0903 (50 nM) (n = 3). (E) Cell differentiation measured by expression of CD11b after treatment with TP-0903 (20 nM and 50 nM) for 72 hours (representative images). (F) Bioluminescence signal (mean ±SEM) and survival (Kaplan-Meier analysis) and spleen weight at study end following treatment with TP-0903 (50 mg/kg) once daily (n = 6) or vehicle (n = 8) in an OCI-AML3–Luc+ NSG mouse xenograft model. Black bars depict treatment days. (G) Inhibition of viability of human primary AML samples with indicated mutations treated with indicated TKI (CellTiterGlo, 72 hours, n = 3). P values were determined using either unpaired 2-tailed Student’s t test (F), 1 way ANOVA (P < 0.002; D) with Dunnett’s multiple comparison test, or log rank test (F; survival curve). Specific P values are indicated within the figure.