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Clonal Selection with RAS Pathway Activation Mediates Secondary Clinical Resistance to Selective FLT3 Inhibition in
Christine M McMahon1, Timothy Ferng2, Jonathan Canaani3
1Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.
Cancer Discovery
|May 16, 2019
Summary
Gilteritinib resistance in FLT3-mutated acute myeloid leukemia (AML) arises from new mutations, often in the RAS/MAPK pathway. This clonal evolution highlights the need for combination therapies to overcome treatment resistance.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Gilteritinib is an FLT3 inhibitor effective in relapsed/refractory FLT3-mutated acute myeloid leukemia (AML).
- Treatment response is often limited by the development of secondary resistance mechanisms.
Purpose of the Study:
- To investigate the molecular mechanisms of gilteritinib resistance in FLT3-mutated AML.
- To analyze clonal evolution and selection patterns during treatment with gilteritinib.
Main Methods:
- Analysis of baseline and progression samples from patients with FLT3-mutated AML treated with gilteritinib.
- Targeted next-generation sequencing and single-cell targeted DNA sequencing.
Main Results:
- Treatment-emergent mutations activating the RAS/MAPK pathway (e.g., in NRAS, KRAS) were identified at progression.
- Secondary FLT3 gatekeeper mutations (F691L) or BCR-ABL1 fusions were less common resistance mechanisms.
- Single-cell sequencing revealed diverse clonal evolution patterns, including RAS mutations in FLT3-mutated subclones and expansion of wild-type FLT3 subclones.
Conclusions:
- Complex and heterogeneous clonal selection and evolution drive clinical resistance to gilteritinib in FLT3-mutated AML.
- Findings support the development of combinatorial targeted therapies for advanced AML to overcome resistance.
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