Ribonucleotide Reductase Inhibition Overcomes FLT3 Inhibitor Resistance in Acute Myeloid Leukemia

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ABSTRACT Internal tandem duplication mutations in FLT3 ( FLT3 ITD ) occur in approximately 30% of patients with acute myeloid leukemia (AML) and are among the most common genetic alterations in this disease. FLT3 ITD is a major driver of AML and is associated with poor clinical outcomes. Although FLT3 inhibitors (FLT3is) have significantly improved outcomes for patients with FLT3 ITD + AML, acquired resistance remains a major barrier to durable clinical benefit. Reactivation of RAS/MAPK signaling, often driven by activating NRAS mutations, is a major mechanism of FLT3i resistance in AML; however, effective strategies to overcome this resistance remain lacking. Here, we identify ribonucleotide reductase (RNR) as a critical therapeutic vulnerability in NRAS -driven FLT3i-resistant FLT3 ITD + AML. Activation of RAS signaling through SPRY3 loss or oncogenic NRAS mutations confers robust resistance to FLT3is, whereas pharmacologic inhibition of RNR with multiple inhibitors, as well as siRNA-mediated RNR suppression, reverses FLT3i resistance and restores FLT3i sensitivity across multiple FLT3 ITD + AML models in vitro . In vivo , clofarabine, an FDA-approved RNR inhibitor (RNRi), significantly overcomes NRAS mutation-driven FLT3i resistance. In combination with FLT3 inhibition, clofarabine markedly suppresses the progression of FLT3i-resistant AML and significantly prolongs survival in cell line-derived xenograft (CDX) models. Importantly, the therapeutic efficacy of the gilteritinib/clofarabine combination was independently validated in two genetically distinct patient-derived xenograft (PDX) models harboring different NRAS mutations, demonstrating robust reduction of leukemia burden and confirming the generalizability of RNR inhibition in primary FLT3i-resistant AML. Together, these findings identify a previously unrecognized therapeutic vulnerability in FLT3i-resistant FLT3 mut + AML and establish RNR inhibition as an effective strategy to overcome FLT3i resistance, providing a strong rationale for the clinical evaluation of RNRis in combination with FLT3is in patients with resistant AML. Significance Although FLT3 inhibitors (FLT3i) are an important therapeutic advance in FLT3 ITD + AML, resistance commonly develops. We identified ribonucleotide reductase (RNR) as a new key vulnerability in NRAS -driven FLT3i-resistant AML and demonstrated that multiple RNRis, including the FDA-approved agent clofarabine, restore FLT3i sensitivity and enhance antileukemic activity, supporting a clinically actionable combination strategy.

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