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Ref Type Journal Article
PMID (28912176)
Authors Ruvolo PP, Ma H, Ruvolo VR, Zhang X, Mu H, Schober W, Hernandez I, Gallardo M, Khoury JD, Cortes J, Andreeff M, Post SM
Title 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.
Journal Vol Issue Date Pages Journal Short Title
Haematologica 102 12 2017 Dec 2048-2057 Haematologica
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
ONO-7475 ONO-7475 2 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
ONO-7475 ONO7475 AXL Inhibitor 30 FLT3 Inhibitor 69 MERTK Inhibitor 13 TYRO3 Inhibitor 7 ONO-7475 inhibits AXL, MERTK, FLT3, and TYRO3, potentially leading to reduced growth and increased apoptosis of tumor cells (PMID: 28912176, PMID: 30501104, PMID: 31953310).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
AXL pos FLT3 exon 14 ins acute myeloid leukemia sensitive ONO-7475 Preclinical - Cell line xenograft Actionable In a preclinical study, ONO-7475 treatment inhibited phosphorylation of Flt3, Erk and S6, induced apoptosis and cell cycle arrest, and reduced viability of acute myeloid leukemia cell lines expressing AXL and harboring FLT3-ITD in culture, and increased median survival in a cell line xenograft model (PMID: 28912176). 28912176
AXL pos FLT3 exon 14 ins acute myeloid leukemia sensitive Cytarabine + ONO-7475 Preclinical - Cell culture Actionable In a preclinical study, ONO-7475 combined with Cytosar-U (cytarabine) treatment resulted in enhanced reduction in viability and induction of apoptosis in acute myeloid leukemia cell lines expressing AXL and harboring FLT3-ITD in culture (PMID: 28912176). 28912176