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Ref Type Journal Article
PMID (34732043)
Authors Post SM, Ma H, Malaney P, Zhang X, Aitken MJL, Mak PY, Ruvolo VR, Yasuhiro T, Kozaki R, Chan LE, Ostermann LB, Konopleva M, Carter BZ, DiNardo C, Andreeff MD, Khoury JD, Ruvolo PP
Title AXL/MERTK inhibitor ONO-7475 potently synergizes with venetoclax and overcomes venetoclax resistance to kill FLT3-ITD acute myeloid leukemia.
Journal Haematologica
Vol
Issue
Date 2021 Nov 04
URL
Abstract Text FMS-like Tyrosine Kinase 3 (FLT3) mutation is associated with poor survival in AML. The specific Anexelekto/MER Tyrosine Kinase (AXL) inhibitor ONO-7475 kills FLT3-mutant acute myeloid leukemia cells with targets including Extracellular-signal Regulated Kinase (ERK) and Myeloid Cell Leukemia 1 (MCL1). ERK and MCL1 are known resistance factors for Venetoclax (ABT-199), a popular drug for AML therapy, prompting the investigation of the efficacy of ONO-7475 in combination with ABT-199 in vitro and in vivo. ONO-7475 synergizes with ABT-199 to potently kill FLT3-mutant acute myeloid leukemia cell lines and primary cells. ONO-7475 is effective against ABT-199-resistant cells including cells that overexpress MCL1. Proteomic analyses revealed that ABT-199-resistant cells expressed elevated levels of pro-growth and anti-apoptotic proteins compared to parental cells, and that ONO-7475 reduced the expression of these proteins in both the parental and ABT-199-resistant cells. ONO-7475 treatment significantly extended survival as a single agent in vivo using acute myeloid leukemia cell lines and PDX models. Compared to ONO-7474 monotherapy, the combination of ONO- 7475/ABT-199 was even more potent in reducing leukemic burden and prolonging survival of mice in both model systems. These results suggest the ONO-7475/ABT-199 combination may be effective for acute myeloid leukemia therapy.

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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 sensitive ONO-7475 Preclinical - Pdx & cell culture Actionable In a preclinical study, ONO-7475 treatment inhibited Erk phosphorylation and cell viability in acute myeloid leukemia cell lines harboring a FLT3-ITD mutation in culture, and reduced leukemia burden and prolonged survival in patient-derived xenograft (PDX) and cell line xenograft models (PMID: 34732043). 34732043
FLT3 exon 14 ins acute myeloid leukemia sensitive ONO-7475 + Venetoclax Preclinical - Pdx & cell culture Actionable In a preclinical study, the combination of ONO-7475 and Venclexta (venetoclax) synergistically inhibited cell viability and induced apoptosis in acute myeloid leukemia cell lines harboring a FLT3-ITD mutation in culture, and reduced leukemia burden and prolonged overall survival in patient-derived xenograft (PDX) and cell line xenograft models with increased efficacy over either agent alone (PMID: 34732043). 34732043