title: FLT3 and CDK4/6 inhibitors: signaling mechanisms and tumor burden in subcutaneous and orthotopic mouse models of acute myeloid leukemia.
abstract: FLT3(ITD) 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 FLT3(ITD) 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.
authors.affiliation: Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, 90089, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Zhang
authors.forename: Cheng-Pang
authors.initials: CP
authors.lastname: Hsu
authors.forename: Jian-Feng
authors.initials: JF
authors.lastname: Lu
authors.forename: Mita
authors.initials: M
authors.lastname: Kuchimanchi
authors.forename: Yu-Nien
authors.initials: YN
authors.lastname: Sun
authors.forename: Ji
authors.initials: J
authors.lastname: Ma
authors.forename: Guifen
authors.initials: G
authors.lastname: Xu
authors.forename: Yilong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Margaret
authors.initials: M
authors.lastname: Weidner
authors.forename: Justin
authors.initials: J
authors.lastname: Huard
authors.forename: David Z
authors.initials: DZ
authors.lastname: D'Argenio
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D000077157:Sorafenib; D047368:Tumor Burden / Q000187:drug effects*; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D052160:Benzothiazoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; C544967:quizartinib; D000077157:Sorafenib; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3; C495902:Cdk4 protein, mouse; C495912:Cdk6 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6