2. Academic Validation
  3. Quizartinib-induced resistance drives clonal emergence of MV4-11 cells with molecular alterations enabling multidrug antileukemic escape

Quizartinib-induced resistance drives clonal emergence of MV4-11 cells with molecular alterations enabling multidrug antileukemic escape

  • Eur J Pharmacol. 2026 May 10:1023:178877. doi: 10.1016/j.ejphar.2026.178877.
Livia Bassani Lins de Miranda 1,  Keli Lima 2,  Diego A Pereira-Martins 3,  Juan Luiz Coelho-Silva 1,  Victoria Tomaz 4,  Luiz Gustavo Ferreira Cortez 4,  Marina de Franca Basto Silva 4,  Rafael Lucas Muniz Guedes 4,  Paulo Vidal Campregher 5,  Dominique Sternadt 3,  Eduardo Magalhães Rego 6,  Fabiola Traina 7,  Jan Jacob Schuringa 3,  João Agostinho Machado-Neto 8
Affiliations

Affiliations

  • 1 Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
  • 2 Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil; Laboratory of Medical Research in Pathogenesis and Target Therapy in Onco-Immuno-Hematology, Department of Internal Medicine, Division of Hematology, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil.
  • 3 Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
  • 4 Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.
  • 5 Hospital Israelita Albert Einstein, São Paulo, SP, Brazil; Genesis Genomics, São Paulo, SP, Brazil.
  • 6 Laboratory of Medical Research in Pathogenesis and Target Therapy in Onco-Immuno-Hematology, Department of Internal Medicine, Division of Hematology, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil; Center for Cell Therapy, Foundation for Research Support of the State of São Paulo, Ribeirão Preto, SP, Brazil.
  • 7 Center for Cell Therapy, Foundation for Research Support of the State of São Paulo, Ribeirão Preto, SP, Brazil; Department of Medical Imaging, Hematology, and Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
  • 8 Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil. Electronic address: [email protected].
PMID: 41997407 DOI: 10.1016/j.ejphar.2026.178877
Abstract

FLT3 inhibitors have become a cornerstone in the treatment of FLT3-mutated acute myeloid leukemia (AML), however, durable clinical responses are frequently limited by the emergence of acquired resistance. In this study, we established and comprehensively characterized a quizartinib-resistant FLT3-ITD AML model to elucidate the molecular and functional mechanisms underlying therapeutic failure. Prolonged exposure of MV4-11 cells to escalating concentrations of quizartinib resulted in the selection of quizartinib resistant clones (MV4-11QR), displaying an increase in IC50 and a shift from cytotoxic to predominantly cytostatic responses. Resistant cells maintained MAPK signaling despite FLT3 inhibition. Global proteomic profiling revealed extensive reprogramming, with enrichment of pathways related to energy metabolism, RNA processing, and translational regulation, accompanied by enhanced mitochondrial respiration and glycolytic capacity. Whole-genome Sequencing identified acquisition of the FLT3D835H mutation and clonal expansion of TP53R248W with loss of the wild-type TP53 allele, indicating strong treatment-driven clonal selection. Functionally, MV4-11QR cells showed broad cross-resistance to clinically relevant agents, including midostaurin, venetoclax, and cytarabine. Importantly, pharmacological targeting of mutant p53 with eprenetapopt or MAPK signaling with trametinib restored sensitivity to quizartinib, inducing synergistic or additive cytotoxic effects and increased Apoptosis. Together, these findings define a multilayered resistance program involving genetic, signaling, and metabolic adaptations and support rational combination strategies to overcome FLT3 Inhibitor resistance in AML.

Keywords

Acute myeloid leukemia; Clonal selection; FLT3 inhibitor resistance; Multidrug resistance; Quizartinib; TP53 mutation.

Figures
Products