{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:03:59Z","timestamp":1785420239951,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,22]]},"group-title":"Cancer Biology","reference-count":49,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["1R01CA255221-01"],"award-info":[{"award-number":["1R01CA255221-01"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100031445","name":"New Jersey Commission on Cancer Research","doi-asserted-by":"crossref","award":["COCR24PRG005"],"award-info":[{"award-number":["COCR24PRG005"]}],"id":[{"id":"10.13039\/100031445","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/04npwsp41","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,22]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Internal tandem duplication mutations in\n                  <jats:italic>FLT3<\/jats:italic>\n                  (\n                  <jats:italic>FLT3<\/jats:italic>\n                  <jats:sup>ITD<\/jats:sup>\n                  ) occur in approximately 30% of patients with acute myeloid leukemia (AML) and are among the most common genetic alterations in this disease.\n                  <jats:italic>FLT3<\/jats:italic>\n                  <jats:sup>ITD<\/jats:sup>\n                  is a major driver of AML and is associated with poor clinical outcomes. Although FLT3 inhibitors (FLT3is) have significantly improved outcomes for patients with\n                  <jats:italic>FLT3<\/jats:italic>\n                  <jats:sup>ITD<\/jats:sup>\n                  + AML, acquired resistance remains a major barrier to durable clinical benefit. Reactivation of RAS\/MAPK signaling, often driven by activating\n                  <jats:italic>NRAS<\/jats:italic>\n                  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\n                  <jats:italic>NRAS<\/jats:italic>\n                  -driven FLT3i-resistant\n                  <jats:italic>FLT3<\/jats:italic>\n                  <jats:sup>ITD<\/jats:sup>\n                  + AML. Activation of RAS signaling through\n                  <jats:italic>SPRY3<\/jats:italic>\n                  loss or oncogenic\n                  <jats:italic>NRAS<\/jats:italic>\n                  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\n                  <jats:italic>FLT3<\/jats:italic>\n                  <jats:sup>ITD<\/jats:sup>\n                  + AML models\n                  <jats:italic>in vitro<\/jats:italic>\n                  .\n                  <jats:italic>In vivo<\/jats:italic>\n                  , clofarabine, an FDA-approved RNR inhibitor (RNRi), significantly overcomes\n                  <jats:italic>NRAS<\/jats:italic>\n                  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\n                  <jats:italic>NRAS<\/jats:italic>\n                  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\n                  <jats:italic>FLT3<\/jats:italic>\n                  <jats:sup>mut<\/jats:sup>\n                  + 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.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance<\/jats:title>\n                  <jats:p>\n                    Although FLT3 inhibitors (FLT3i) are an important therapeutic advance in\n                    <jats:italic>FLT3<\/jats:italic>\n                    <jats:sup>ITD<\/jats:sup>\n                    + AML, resistance commonly develops. We identified ribonucleotide reductase (RNR) as a new key vulnerability in\n                    <jats:italic>NRAS<\/jats:italic>\n                    -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.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.07.21.736123","type":"posted-content","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T21:20:19Z","timestamp":1784755219000},"source":"Crossref","is-referenced-by-count":0,"title":["Ribonucleotide Reductase Inhibition Overcomes FLT3 Inhibitor Resistance in Acute Myeloid Leukemia"],"prefix":"10.64898","author":[{"given":"Zhen","family":"Tian","sequence":"first","affiliation":[{"name":"Coriell Institute for Medical Research, Camden, NJ, 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