Quizartinib-induced resistance drives clonal emergence of MV4-11 cells with molecular alterations enabling multidrug antileukemic escape
When leukemia develops resistance to one drug, adding a second drug targeting the resistance mechanism restores sensitivity in lab models.
Using a stepwise drug escalation model, quizartinib-resistant FLT3-ITD AML cells were found to acquire gatekeeper FLT3-D835H and gain-of-function TP53-R248W mutations with broad cross-resistance to midostaurin, venetoclax, and cytarabine. Targeting mutant p53 with eprenetapopt or MAPK signaling with trametinib restored drug sensitivity, providing a rational combination approach for relapsed/refractory disease.
What the study was
- Study design
- Preclinical in vitro resistance model with WGS and proteomic profiling
- Population
- FLT3-ITD AML cell line (MV4-11)
- Category
- Drug Development
- Maturity
- Exploratory
- Journal
- European Journal of Pharmacology
Why it surfaced
Comprehensive resistance characterization (WGS + proteomics) with actionable combination strategies (eprenetapopt+quizartinib) relevant to clinical management of relapsed FLT3+ AML.
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