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
Figure 4
TP-0903 overcomes drug resistance due to bone marrow microenvironment–mediated factors.
