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A-B . Clofarabine treatment effectively reversed AC220 (A) and gilteritinib (B) resistance in SPRY3 KO/ FLT3 ITD + MV4-11 AML cells. C-D. Clofarabine treatment effectively reversed AC220 (C) and gilteritinib (D) resistance in NRAS mut / FLT3 ITD + MV4-11 AML cells. E. Clofarabine alone exhibited minimal cytotoxicity in MV4-11 AML cells. F-H. Additional RNRis, including fludarabine, <t>gemcitabine,</t> and hydroxyurea, also effectively reversed gilteritinib resistance in NRAS mut / FLT3 ITD + MV4-11 AML cells. I . Cladribine, a clinically approved purine nucleoside analog and indirect RNR inhibitor, reversed FLT3i resistance in NRAS mut / FLT3 ITD + AML cells. J. Triapine, a potent RNRi, reversed FLT3i resistance in NRAS mut / FLT3 ITD + MV4-11 AML cells. K. Nelarabine, an RNR activator, induced FLT3i resistance in NRAS WT MV4-11 AML cells; this effect was reversed by clofarabine. Data represent the means ± SD of three replicates.
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A-B . Clofarabine treatment effectively reversed AC220 (A) and gilteritinib (B) resistance in SPRY3 KO/ FLT3 ITD + MV4-11 AML cells. C-D. Clofarabine treatment effectively reversed AC220 (C) and gilteritinib (D) resistance in NRAS mut / FLT3 ITD + MV4-11 AML cells. E. Clofarabine alone exhibited minimal cytotoxicity in MV4-11 AML cells. F-H. Additional RNRis, including fludarabine, <t>gemcitabine,</t> and hydroxyurea, also effectively reversed gilteritinib resistance in NRAS mut / FLT3 ITD + MV4-11 AML cells. I . Cladribine, a clinically approved purine nucleoside analog and indirect RNR inhibitor, reversed FLT3i resistance in NRAS mut / FLT3 ITD + AML cells. J. Triapine, a potent RNRi, reversed FLT3i resistance in NRAS mut / FLT3 ITD + MV4-11 AML cells. K. Nelarabine, an RNR activator, induced FLT3i resistance in NRAS WT MV4-11 AML cells; this effect was reversed by clofarabine. Data represent the means ± SD of three replicates.
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A-B . Clofarabine treatment effectively reversed AC220 (A) and gilteritinib (B) resistance in SPRY3 KO/ FLT3 ITD + MV4-11 AML cells. C-D. Clofarabine treatment effectively reversed AC220 (C) and gilteritinib (D) resistance in NRAS mut / FLT3 ITD + MV4-11 AML cells. E. Clofarabine alone exhibited minimal cytotoxicity in MV4-11 AML cells. F-H. Additional RNRis, including fludarabine, <t>gemcitabine,</t> and hydroxyurea, also effectively reversed gilteritinib resistance in NRAS mut / FLT3 ITD + MV4-11 AML cells. I . Cladribine, a clinically approved purine nucleoside analog and indirect RNR inhibitor, reversed FLT3i resistance in NRAS mut / FLT3 ITD + AML cells. J. Triapine, a potent RNRi, reversed FLT3i resistance in NRAS mut / FLT3 ITD + MV4-11 AML cells. K. Nelarabine, an RNR activator, induced FLT3i resistance in NRAS WT MV4-11 AML cells; this effect was reversed by clofarabine. Data represent the means ± SD of three replicates.
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A-B . Clofarabine treatment effectively reversed AC220 (A) and gilteritinib (B) resistance in SPRY3 KO/ FLT3 ITD + MV4-11 AML cells. C-D. Clofarabine treatment effectively reversed AC220 (C) and gilteritinib (D) resistance in NRAS mut / FLT3 ITD + MV4-11 AML cells. E. Clofarabine alone exhibited minimal cytotoxicity in MV4-11 AML cells. F-H. Additional RNRis, including fludarabine, <t>gemcitabine,</t> and hydroxyurea, also effectively reversed gilteritinib resistance in NRAS mut / FLT3 ITD + MV4-11 AML cells. I . Cladribine, a clinically approved purine nucleoside analog and indirect RNR inhibitor, reversed FLT3i resistance in NRAS mut / FLT3 ITD + AML cells. J. Triapine, a potent RNRi, reversed FLT3i resistance in NRAS mut / FLT3 ITD + MV4-11 AML cells. K. Nelarabine, an RNR activator, induced FLT3i resistance in NRAS WT MV4-11 AML cells; this effect was reversed by clofarabine. Data represent the means ± SD of three replicates.
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A-B . Clofarabine treatment effectively reversed AC220 (A) and gilteritinib (B) resistance in SPRY3 KO/ FLT3 ITD + MV4-11 AML cells. C-D. Clofarabine treatment effectively reversed AC220 (C) and gilteritinib (D) resistance in NRAS mut / FLT3 ITD + MV4-11 AML cells. E. Clofarabine alone exhibited minimal cytotoxicity in MV4-11 AML cells. F-H. Additional RNRis, including fludarabine, gemcitabine, and hydroxyurea, also effectively reversed gilteritinib resistance in NRAS mut / FLT3 ITD + MV4-11 AML cells. I . Cladribine, a clinically approved purine nucleoside analog and indirect RNR inhibitor, reversed FLT3i resistance in NRAS mut / FLT3 ITD + AML cells. J. Triapine, a potent RNRi, reversed FLT3i resistance in NRAS mut / FLT3 ITD + MV4-11 AML cells. K. Nelarabine, an RNR activator, induced FLT3i resistance in NRAS WT MV4-11 AML cells; this effect was reversed by clofarabine. Data represent the means ± SD of three replicates.

Journal: bioRxiv

Article Title: Ribonucleotide Reductase Inhibition Overcomes FLT3 Inhibitor Resistance in Acute Myeloid Leukemia

doi: 10.64898/2026.07.21.736123

Figure Lengend Snippet: A-B . Clofarabine treatment effectively reversed AC220 (A) and gilteritinib (B) resistance in SPRY3 KO/ FLT3 ITD + MV4-11 AML cells. C-D. Clofarabine treatment effectively reversed AC220 (C) and gilteritinib (D) resistance in NRAS mut / FLT3 ITD + MV4-11 AML cells. E. Clofarabine alone exhibited minimal cytotoxicity in MV4-11 AML cells. F-H. Additional RNRis, including fludarabine, gemcitabine, and hydroxyurea, also effectively reversed gilteritinib resistance in NRAS mut / FLT3 ITD + MV4-11 AML cells. I . Cladribine, a clinically approved purine nucleoside analog and indirect RNR inhibitor, reversed FLT3i resistance in NRAS mut / FLT3 ITD + AML cells. J. Triapine, a potent RNRi, reversed FLT3i resistance in NRAS mut / FLT3 ITD + MV4-11 AML cells. K. Nelarabine, an RNR activator, induced FLT3i resistance in NRAS WT MV4-11 AML cells; this effect was reversed by clofarabine. Data represent the means ± SD of three replicates.

Article Snippet: Gilteritinib (HY-12432), AC220 (quizartinib, HY-13001), clofarabine (HY-A0005), fludarabine (HY-B0069), gemcitabine (HY-17026), hydroxyurea (HY-B0313), cladribine (HY-13599), triapine (HY-10082), nelarabine (HY-13701), doxycycline (HY-N0565), and D-luciferin potassium (HY-12591B) were purchased from MedChemExpress.

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