Purpose: Acute myeloid leukemia (AML) is characterized by frequent mutation of 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. Here, we investigated the antileukemia efficacy of co-targeting FLT3 and MDM2 with quizartinib and milademetan (Q/M) in FLT3-internal tandem duplication (ITD) AML cell lines, xenograft and patient-derived xenograft (PDX) models, and a phase 1 clinical trial.
Methods: Preclinical studies used human and murine cell lines carrying FLT3-ITD, and/or TKD mutations and TP53 WT/knockdown, leukemia cell xenograft models and a PDX model. Assays were conducted using milademetan (DS-3032b) and murine-specific MDM2i (DS-5272). An open-label, phase 1, dose-escalation clinical trial (ClinicalTrials.gov NCT03552029) was conducted.
Results: 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 1 clinical data indicated favorable safety and tolerability for the Q/M combination treatment. Complete responses with incomplete hematologic recovery were achieved in 40% of relapsed/refractory AML patients. Unsupervised single-cell proteomics analysis showed Q/M treatment decreased the expression of prosurvival (pERK, pAKT, Mcl-1) proteins and activated protein signaling downstream of p53 including PUMA. YTHDF2 was increased post therapy in resistant cells. Q/M combination demonstrated higher activity in CD34+ versus CD34- leukemia blasts.
Conclusions: Preclinical and mechanistic rationale and preliminary clinical data support the future development of MDM2/FLT3 targeting strategies for FLT3-mutant AML.