Adaptor-mediated rewiring of FLT3 signaling engages p38 MAPK to sustain gilteritinib resistance in acute myeloid leukemia.
Blocking a stress pathway alongside standard leukemia drugs suppresses drug-resistant AML in lab models, suggesting a rational new combination approach.
Using a CRISPR-Cas9 kinome-wide screen in gilteritinib-resistant AML cells, this study identifies p38α (MAPK14) rather than ERK as the key stress-adaptive dependency maintained through adaptor-mediated FLT3 signaling rewiring via p46-SHC1. Pharmacologic p38 inhibition synergizes with gilteritinib to suppress resistant leukemic growth, offering a mechanistic basis for rational combination therapy in FLT3-inhibitor-refractory AML.
What the study was
- Study design
- Mechanistic study with CRISPR-Cas9 kinome screen, in vitro and in vivo validation, primary AML samples
- Population
- FLT3-mutated AML (gilteritinib-resistant cell lines, murine models, primary patient samples)
- Category
- Drug Development
- Maturity
- Exploratory
- Journal
- Leukemia
Why it surfaced
CRISPR kinome screen revealing non-canonical p38α dependency in gilteritinib-resistant AML with immediate combination therapy rationale; Leukemia journal, high clinical unmet need.
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