Reference Detail

Ref Type

Journal Article

PMID

(33658483)

Authors

Eisfelder BJ, Saygin C, Wynne J, Colton MW, Fischietti M, Beauchamp EM, Cheng JX, Odenike O, Roboz G, Alachkar H, Stock W

Title

OTS167 blocks FLT3 translation and synergizes with FLT3 inhibitors in FLT3 mutant acute myeloid leukemia.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Blood cancer journal	11	3	2021 Mar 03	48	Blood Cancer J

URL

Abstract Text

Internal tandem duplication (-ITD) mutations of Fms-like tyrosine kinase 3 (FLT3) provide growth and pro-survival signals in the context of established driver mutations in FLT3 mutant acute myeloid leukemia (AML). Maternal embryonic leucine zipper kinase (MELK) is an aberrantly expressed gene identified as a target in AML. The MELK inhibitor OTS167 induces cell death in AML including cells with FLT3 mutations, yet the role of MELK and mechanisms of OTS167 function are not understood. OTS167 alone or in combination with tyrosine kinase inhibitors (TKIs) were used to investigate the effect of OTS167 on FLT3 signaling and expression in human FLT3 mutant AML cell lines and primary cells. We describe a mechanism whereby OTS167 blocks FLT3 expression by blocking FLT3 translation and inhibiting phosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and eukaryotic translation initiation factor 4B (eIF4B). OTS167 in combination with TKIs results in synergistic induction of FLT3 mutant cell death in FLT3 mutant cell lines and prolonged survival in a FLT3 mutant AML xenograft mouse model. Our findings suggest signaling through MELK is necessary for the translation and expression of FLT3-ITD, and blocking MELK with OTS167 represents a viable therapeutic strategy for patients with FLT3 mutant AML.

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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

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

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
FLT3 exon 14 ins	acute myeloid leukemia	predicted - sensitive	OTS167	Preclinical - Patient cell culture	Actionable	In a preclinical study, OTS167 treatment induced cell death in patient-derived acute myeloid leukemia cells harboring FLT3-ITD in culture (PMID: 33658483).	33658483
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	Gilteritinib + OTS167	Preclinical - Cell line xenograft	Actionable	In a preclinical study, combination treatment with OTS167 and Xospata (gilteritinib) synergistically inhibited cell viability and led to inhibition of colony formation in acute myeloid leukuemia (AML) cell lines harboring a FLT3-ITD and patient-derived AML cell lines with a FLT3-ITD in culture, and led to improved overall survival and reduction of leukemia burden in a cell line xenograft model (PMID: 33658483).	33658483