Mitochondrial integrated stress response activation creates a therapeutic vulnerability to MCL-1 inhibition in acute myeloid leukemia.
Targeting mitochondrial stress plus anti-cancer drug MCL-1 inhibitor extends survival in aggressive leukemia models, offering potential new combination strategy.
St. Jude investigators demonstrate that mitochondrial electron transport chain complex I inhibition triggers an integrated stress response (HRI kinase → DELE1 → ATF4) that creates synthetic lethality with MCL-1 inhibitors in AML. Co-targeting CI and MCL-1 significantly prolongs survival in KMT2A-rearranged PDX mouse models, providing a mechanistic rationale and preclinical proof-of-concept for overcoming MCL-1 inhibitor resistance in high-risk AML.
What the study was
- Study design
- Preclinical: AML cell lines + patient-derived xenografts + in vivo mouse models
- Population
- AML cell lines and patient-derived xenograft (PDX) samples, KMT2A-rearranged subtype
- Category
- Drug Development
- Maturity
- Exploratory
- Journal
- Cell Death and Disease
Why it surfaced
Novel mechanistic rationale for MCL-1 + CI co-inhibition in high-risk AML; St. Jude Research Hospital; preclinical cap applied (max 5); KMT2A-r AML is an unmet need.
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