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|Ref Type||Journal Article|
|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.|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|ONO-7475||ONO7475||AXL Inhibitor 28 FLT3 Inhibitor 61 MERTK Inhibitor 13 TYRO3 Inhibitor 8||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||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|
|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|