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TP-0903 is active in models of drug-resistant acute myeloid leukemia
Jae Yoon Jeon1, Daelynn R Buelow1, Dominique A Garrison1
1Division of Pharmaceutics and Pharmacology, College of Pharmacy.
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.
Insights
TP-0903 shows strong activity against drug-resistant acute myeloid leukemia (AML) models. This multikinase inhibitor targets key signaling pathways and overcomes common resistance mechanisms, offering potential for treating heterogeneous AML.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Acute myeloid leukemia (AML) treatment is complicated by clonal heterogeneity and drug resistance.
- Targeting key signaling pathways and cell cycle regulators is crucial for effective AML therapy.
Purpose of the Study:
- To evaluate the preclinical efficacy of TP-0903, a novel multikinase inhibitor, against various models of drug-resistant AML.
- To investigate TP-0903's activity against AML with specific mutations and in the context of the bone marrow microenvironment.
Main Methods:
- Biochemical and cellular assays were used to assess TP-0903's activity against protein kinases (STAT, AKT, ERK) and cell cycle regulators.
- In vitro and in vivo studies were conducted using multiple models of drug-resistant FLT3 mutant AML.
- Ex vivo studies evaluated TP-0903's activity in primary AML cells with recurrent mutations.
Main Results:
- TP-0903 demonstrated potent activity against FLT3 mutant AML, including models with the F691L gatekeeper mutation and resistance mediated by the bone marrow microenvironment.
- The compound showed preclinical efficacy in AML models harboring FLT3-ITD, IDH2, and NRAS mutations.
- TP-0903 exhibited ex vivo activity against primary AML cells with poor-prognosis mutations like MLL-PTD, ASXL1, SRSF2, and WT1.
Conclusions:
- TP-0903 is a multikinase inhibitor with significant preclinical activity against diverse drug-resistant AML models.
- Its ability to overcome multiple resistance mechanisms suggests potential for immediate clinical impact in heterogeneous AML populations.