FLT3 and CDK4/6 inhibitors: Signaling mechanisms and tumor burden in subcutaneous and orthotopic mouse models of acute myeloid leukemia
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FLT3ITD subtype acute myeloid leukemia (AML) has a poor prognosis with currently available therapies. A number of small molecule inhibitors of FLT3 and/or CDK4/6 are currently under development. A more complete and quantitative understanding of the mechanisms of action of FLT3 and CDK4/6 inhibitors may better inform the development of current and future compounds that act on one or both of the molecular targets, and thus may lead to improved treatments for AML. In this study, we investigated in both subcutaneous and orthotopic AML mouse models, the mechanisms of action of three FLT3 and/or CDK4/6 inhibitors: AMG925 (Amgen), sorafenib (Bayer and Onyx), and quizartinib (Ambit Biosciences). A composite model was developed to integrate the plasma pharmacokinetics of these three compounds on their respective molecular targets, the coupling between the target pathways, as well as the resulting effects on tumor burden reduction in the subcutaneous xenograft model. A sequential modeling approach was used, wherein model structures and estimated parameters from upstream processes (e.g. PK, cellular signaling) were fixed for modeling subsequent downstream processes (cellular signaling, tumor burden). Pooled data analysis was employed for the plasma PK and cellular signaling modeling, while population modeling was applied to the tumor burden modeling. The resulting model allows the decomposition of the relative contributions of FLT3ITD and CDK4/6 inhibition on downstream signaling and tumor burden. In addition, the action of AMG925 on cellular signaling and tumor burden was further studied in an orthotopic tumor mouse model more closely representing the physiologically relevant environment for AML.
KeywordsFLT3 inhibitors CDK4/6 inhibitors Acute myeloid leukemia STAT5 Rb Subcutaneous tumor Orthotopic tumor
We gratefully acknowledge Kathy Keegan for her contribution to mouse tumor studies. We also acknowledge Ruta Phadnis and Tim Carlson for their contribution to pharmacokinetic studies. We appreciate the helpful comments provided by Jordan Fridman at Flexus Biosciences, Inc. This work was supported by Amgen Inc., as well as by Grant NIH/NIBIB P41-EB001978 (DZD).
Conflict of interest
Y. Zhang and D.Z. D’Argenio declare no conflict of interests. J.-F. Lu is an employee of Askgene Pharma, and the remaining authors are employees of Amgen Inc.
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