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Ref Type Journal Article
PMID (40327322)
Authors Zhang W, Li L, Muftuoglu M, Basyal M, Togashi N, Iwanaga K, Tanzawa F, Numata M, Bixby DL, Erba HP, Podoltsev N, Schiller GJ, Kumar P, Lesegretain A, Isoyama T, Seki T, Daver N, Andreeff M
Title Synergistic Activity of Combined FLT3-ITD and MDM2 Inhibition with Quizartinib and Milademetan in FLT3-ITD Mutant/TP53 Wild-type Acute Myeloid Leukemias.
Journal Vol Issue Date Pages Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research 31 14 2025 Jul 15 3033-3047 Clin Cancer Res
URL
Abstract Text Acute myeloid leukemia (AML) is characterized by frequent mutations in FMS-like tyrosine kinase 3 (FLT3), overexpression of murine double minute 2 (MDM2), and TP53 wild-type (WT). Monotherapies targeting FLT3 frequently result in the development of resistant disease. In this study, we investigated the antileukemic efficacy of co-targeting FLT3 and MDM2 with quizartinib and milademetan (Q/M) in FLT3 internal tandem duplication (FLT3-ITD) AML cell lines, xenograft and patient-derived xenograft (PDX) models, and a phase I clinical trial.Preclinical studies used human and murine cell lines carrying FLT3-ITD and/or tyrosine kinase domain mutations, TP53 WT/knockdown, leukemia cell xenograft models, and a PDX model. Assays were conducted using milademetan (DS-3032b) and murine-specific MDM2 inhibitor (DS-5272). An open-label, phase I, dose-escalation clinical trial (ClinicalTrials.gov NCT03552029) was conducted.Dual inhibition of FLT3-ITD and MDM2 synergistically induced apoptosis in FLT3-ITD/TP53 WT AML and venetoclax-resistant cell lines, reduced tumor burden, and improved survival in xenograft and PDX models of FLT3-ITD AML. Phase I clinical data indicated favorable safety and tolerability for the Q/M combination treatment. Complete responses with incomplete hematologic recovery were achieved in 40% of patients with relapsed/refractory AML. Unsupervised single-cell proteomic analysis showed that Q/M treatment decreased the expression of prosurvival proteins (p-ERK, p-AKT, and Mcl-1) and activated protein signaling downstream of p53 including p53 upregulated modulator of apoptosis. YTHDF2 was increased after therapy in resistant cells. The Q/M combination demonstrated higher activity in CD34+ versus CD34- leukemia blasts.Preclinical and mechanistic rationale and preliminary clinical data support the future development of MDM2/FLT3-targeting strategies for 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 TP53 wild-type acute myeloid leukemia sensitive Milademetan + Quizartinib Phase I Actionable In a Phase I trial, combination of Vanflyta (quizartinib) and Milademetan led to a complete response with incomplete hematologic recovery (CRi) in 40% (4/10) and stable disease (SD) in 30% of patients with TP53 wild-type acute myeloid leukemia harboring a FLT3-ITD, with a CRi of 50% (3/6) at the recommended dose; and the combination inhibited Flt3 signaling and synergistically induced apoptosis in culture and decreased leukemia growth in a cell line xenograft model (PMID: 40327322; NCT03552029). 40327322
FLT3 exon 14 ins FLT3 D835Y TP53 wild-type acute myeloid leukemia sensitive Milademetan + Quizartinib Preclinical - Pdx Actionable In a preclinical study, treatment with the combination of Vanflyta (quizartinib) and Milademetan decreased leukemia burden and improved survival compared to either drug alone in a patient-derived xenograft (PDX) model of TP53 wild-type acute myeloid leukemia harboring a FLT3-ITD mutation and FLT3 D835Y (PMID: 40327322). 40327322