Anexelekto/MER tyrosine kinase inhibitor ONO-7475 arrests growth and kills FMS-like tyrosine kinase 3-internal tandem duplication mutant acute myeloid leukemia cells by diverse mechanisms
Peter P. Ruvolo,
Huaxian Ma,
Vivian R. Ruvolo,
Xiaorui Zhang,
Hong Mu,
Wendy Schober,
Ivonne Hernandez,
Miguel Gallardo,
Joseph D. Khoury,
Jorge Cortes,
Michael Andreeff,
Sean M. Post
Affiliations
Peter P. Ruvolo
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Section of Molecular Hematology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Huaxian Ma
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Vivian R. Ruvolo
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Section of Molecular Hematology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Xiaorui Zhang
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Hong Mu
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Section of Molecular Hematology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Wendy Schober
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Section of Molecular Hematology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Ivonne Hernandez
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Section of Molecular Hematology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Miguel Gallardo
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Joseph D. Khoury
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Jorge Cortes
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Michael Andreeff
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Section of Molecular Hematology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Sean M. Post
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Nearly one-third of patients with acute myeloid leukemia have FMS-like tyrosine kinase 3 mutations and thus have poor survival prospects. Receptor tyrosine kinase anexelekto is critical for FMS-like tyrosine kinase 3 signaling and participates in FMS-like tyrosine kinase 3 inhibitor resistance mechanisms. Thus, strategies targeting anexelekto could prove useful for acute myeloid leukemia therapy. ONO-7475 is an inhibitor with high specificity for anexelekto and MER tyrosine kinase. Herein, we report that ONO-7475 potently arrested growth and induced apoptosis in acute myeloid leukemia with internal tandem duplication mutation of FMS-like tyrosine kinase 3. MER tyrosine kinase-lacking MOLM13 cells were sensitive to ONO-7475, while MER tyrosine kinase expressing OCI-AML3 cells were resistant, suggesting that the drug acts via anexelekto in acute myeloid leukemia cells. Reverse phase protein analysis of ONO-7475 treated cells revealed that cell cycle regulators like cyclin dependent kinase 1, cyclin B1, polo-like kinase 1, and retinoblastoma were suppressed. ONO-7475 suppressed cyclin dependent kinase 1, cyclin B1, polo-like kinase 1 gene expression suggesting that anexelekto may regulate the cell cycle, at least in part, via transcriptional mechanisms. Importantly, ONO-7475 was effective in a human FMS-like tyrosine kinase 3 with internal tandem duplication mutant murine xenograft model. Mice fed a diet containing ONO-7475 exhibited significantly longer survival and, interestingly, blocked leukemia cell infiltration in the liver. In summary, ONO-7475 effectively kills acute myeloid leukemia cells in vitro and in vivo by mechanisms that involve disruption of diverse survival and proliferation pathways.
