Quizartinib-induced resistance drives clonal emergence of MV4-11 cells with molecular alterations enabling multidrug antileukemic escape
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.
Authors
- João Agostinho Machado‐Neto (ORCID: https://orcid.org/0000-0002-2937-8109)
- Jan Jacob Schuringa (ORCID: https://orcid.org/0000-0001-8452-8555)
- Victoria Tomaz
- Paulo Vidal Campregher (ORCID: https://orcid.org/0000-0001-6005-405X)
- Dominique Sternadt (ORCID: https://orcid.org/0000-0003-3946-1368)
- Eduardo Magalhães Rego (ORCID: https://orcid.org/0000-0003-1567-4086)
- Fabı́ola Traina (ORCID: https://orcid.org/0000-0003-4258-289X)
- Marina de França (ORCID: https://orcid.org/0000-0003-0485-8242)
- Rafael Lucas Muniz Guedes (ORCID: https://orcid.org/0000-0002-9163-6674)
- Lívia Bassani Lins de Miranda (ORCID: https://orcid.org/0000-0001-6635-0247)
- Diego A. Pereira-Martins
- Keli Lima
- Luiz Gustavo Ferreira Cortez
Institutions
- University Medical Center Groningen (NL)
- University of Groningen (NL)
- Universidade de São Paulo (BR)
- Hospital Israelita Albert Einstein (BR)
- Clinics Hospital of Ribeirão Preto (BR)
- Institute of Biomedical Science (GB)
Publication Details
- Journal
- European Journal of Pharmacology
- Published
- 2026-04-15
- DOI
- https://doi.org/10.1016/j.ejphar.2026.178877
- Primary Topic
- Chronic Myeloid Leukemia Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Conselho Nacional de Desenvolvimento Científico e Tecnológico