High-throughput proteomic profiling reveals mechanisms of action of AMG925, a dual FLT3-CDK4/6 kinase inhibitor targeting AML and AML stem/progenitor cells

• Published in: Annals of hematology 2021-06, Vol.100 (6), p.1485-1496
• Main Authors: Zeng, Zhihong, Ly, Charlie, Daver, Naval, Cortes, Jorge, Kantarjian, Hagop M., Andreeff, Michael, Konopleva, Marina
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Cell Line, Tumor; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; fms-Like Tyrosine Kinase 3 - antagonists & inhibitors; fms-Like Tyrosine Kinase 3 - genetics; Hematology; Humans; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - pathology; Medicine; Medicine & Public Health; Mice; Mice, Inbred NOD; Mice, SCID; Mutation; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oncology; Original Article; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proteomics
• ISSN: 0939-5555; 1432-0584; 1432-0584
• DOI: 10.1007/s00277-021-04493-0

FLT3 mutations, which are found in a third of patients with acute myeloid leukemia (AML), are associated with poor prognosis. Responses to currently available FLT3 inhibitors in AML patients are typically transient and followed by disease recurrence. Thus, FLT3 inhibitors with new inhibitory mechanisms are needed to improve therapeutic outcomes. AMG925 is a novel, potent, small-molecule dual inhibitor of FLT3 and CDK4/6. In this study. we determined the antileukemic effects and mechanisms of action of AMG925 in AML cell lines and primary samples, in particular AML stem/progenitor cells. AMG925 inhibited cell growth and promoted apoptosis in AML cells with or without FLT3 mutations. Reverse-phase protein array profiling confirmed its on-target effects on FLT3-CDK4/6–regulated pathways and identified unrevealed signaling network alterations in AML blasts and stem/progenitor cells in response to AMG925. Mass cytometry identified pathways that may confer resistance to AMG925 in phenotypically defined AML stem/progenitor cells and demonstrated that combined blockade of FLT3-CDK4/6 and AKT/mTOR signaling facilitated stem cell death. Our findings provide a rationale for the mechanism-based inhibition of FLT3-CDK4/6 and for combinatorial approaches to improve the efficacy of FLT3 inhibition in both FLT3 wild-type and FLT3 -mutated AML.