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.
Highlights
Acute myeloid leukemia (AML) is characterized by the aberrant proliferation and impaired differentiation of myeloid cells
NPM1 mutations are considered recurrent in AML, and while harboring NPM1 mutations align with a favorable risk category, it is no longer considered favorable in the presence of an FLT3-ITD mutation [4]
Since TP-0903 was shown to inhibit FLT3, we evaluated that activity of TP-0903 against FLT3-ITD and tyrosine kinase domain (TKD) mutants
Summary
Acute myeloid leukemia (AML) is characterized by the aberrant proliferation and impaired differentiation of myeloid cells. It is a heterogeneous disease with multiple molecular abnormalities. Recent developments in genomic sequencing technologies have made it possible to deep sequence AML samples and profile the mutational spectrum. With this information, guidelines have been developed to assign patients to prognostic risk groups based on their individual genetic alterations and provide guidance to tailor treatments to risk category [4]. Clonal heterogeneity of the disease makes AML difficult to treat, and agents with selective activity are prone to clonal selection and drug resistance
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
