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

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2048-2057
Number of pages10
JournalHaematologica
Volume102
Issue number12
DOIs
StatePublished - Nov 30 2017

ASJC Scopus subject areas

  • Hematology

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

  • Cite this

    Ruvolo, P. P., Ma, H., Ruvolo, V. R., Zhang, X., Mu, H., Schober, W., Hernandez, I., Gallardo, M., Khoury, J. D., Cortes, J., Andreeff, M., & Post, S. M. (2017). 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. Haematologica, 102(12), 2048-2057. https://doi.org/10.3324/haematol.2017.168856