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Updated: Aug 5, 2026
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Comet Assay to Quantify DNA Damage in FLT3 Mutant-expressing 32D Cells after Exposure to Type I and Type II FLT3 Inhibitors
Published on: October 17, 2025
Ribonucleotide Reductase Inhibition Overcomes FLT3 Inhibitor Resistance in Acute Myeloid Leukemia
Biorxiv : the Preprint Server for Biology
|August 1, 2026
Summary
FLT3 inhibitors are effective for acute myeloid leukemia (AML), but resistance develops. Targeting ribonucleotide reductase (RNR) with inhibitors like clofarabine can overcome this resistance, restoring FLT3 inhibitor sensitivity in NRAS-driven AML.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Internal tandem duplication (ITD) mutations in FLT3 occur in 30% of acute myeloid leukemia (AML) patients, driving disease progression and poor outcomes.
- FLT3 inhibitors (FLT3is) improve outcomes for FLT3-ITD+ AML, but acquired resistance, often via RAS/MAPK reactivation (e.g., NRAS mutations), limits durable benefit.
- Effective strategies to overcome FLT3 inhibitor resistance in AML are lacking.
Purpose of the Study:
- To identify novel therapeutic vulnerabilities in NRAS-driven FLT3 inhibitor-resistant FLT3-ITD+ AML.
- To evaluate the efficacy of targeting ribonucleotide reductase (RNR) as a strategy to overcome FLT3 inhibitor resistance.
Main Methods:
- Investigated the role of RAS signaling and identified RNR as a vulnerability in FLT3 inhibitor-resistant AML models.
- Utilized pharmacologic RNR inhibitors (including FDA-approved clofarabine) and siRNA-mediated RNR suppression in vitro.
- Assessed the efficacy of clofarabine, alone and in combination with FLT3 inhibitors, in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models in vivo.
Main Results:
- Activation of RAS signaling via SPRY3 loss or NRAS mutations confers resistance to FLT3is.
- Pharmacologic RNR inhibition and RNR suppression restored FLT3 inhibitor sensitivity in vitro.
- The RNR inhibitor clofarabine overcame NRAS mutation-driven FLT3 inhibitor resistance in vivo, significantly prolonging survival in CDX models.
- The combination of gilteritinib and clofarabine demonstrated efficacy in genetically distinct PDX models with NRAS mutations, reducing leukemia burden.
Conclusions:
- Ribonucleotide reductase (RNR) is a critical therapeutic vulnerability in NRAS-driven FLT3 inhibitor-resistant FLT3-ITD+ AML.
- RNR inhibition, particularly with clofarabine, is an effective strategy to overcome FLT3 inhibitor resistance in AML.
- Combination therapy with RNR inhibitors and FLT3 inhibitors warrants clinical evaluation for patients with resistant AML.
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