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Uncovering pre-sensitizing agents to FLT3 inhibitors in acute myeloid leukemia with ReSisTrace lineage tracing

GSE306484 Homo sapiens Expression profiling by high throughput sequencing 6 samples Submitted 2025/11/13 Platform GPL24676
Summary
FLT3 inhibitors have significantly advanced the treatment of aggressive FLT3-mutated acute myeloid leukemia (AML), yet the development of resistance remains a major therapeutic challenge. Using the single-cell lineage-tracing method ReSisTrace, we identified transcriptional signatures distinguishing pre-resistant from pre-sensitive AML cells exposed to midostaurin or quizartinib. Targeting the pre-resistance gene GSPT1 with a CC-90009 degrader synergized with FLT3 inhibitors in AML cell lines, patient samples, and a PDX model, significantly improving survival. W further identified small molecules, including vistusertib (mTOR inhibitor), linsitinib (IGF1R/INSR inhibitor), and meisoindigo (IGF1R/Src inhibitor), capable of reversing pre-resistance transcriptional programs and shifting cells toward a FLT3 inhibitor-sensitive state. In summary, ReSisTrace unveils pre-existing transcriptional features of treatment vulnerability in hematological cancers, and elucidates novel strategies for enhancing FLT3 inhibitor treatment efficacy in FLT3-ITD-positive AML.
Published in
Single-Cell Lineage Tracing Uncovers Resistance Signatures and Sensitizing Strategies to FLT3 Inhibitors in Acute Myeloid Leukemia
Eriksson J, Zheng S, Popa M et al. · Cancer research 2026 · PMID 41270153 · doi:10.1158/0008-5472.CAN-24-3753
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Also filed as BioProject PRJNA1310965 and SRA study SRP612802. Searching any of these in the dataset finder brings you back here.

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