Resistance to decitabine and 5-azacytidine emerges from adaptive responses of the pyrimidine metabolism network
Resistance to decitabine and 5-azacytidine emerges from adaptive responses of the pyrimidine metabolism network
ABSTRACT Mechanisms-of-resistance to decitabine and 5-azacytidine, mainstay treatments for myeloid malignancies, require investigation and countermeasures. Both are nucleoside analog pro-drugs processed by pyrimidine metabolism into a nucleotide analog that depletes the key epigenetic regulator DNA methyltranseferase 1 (DNMT1). We report here that DNMT1 protein, although substantially depleted (~50%) in patients’ bone marrows at response, rebounded at relapse, and explaining this, we found pyrimidine metabolism gene expression shifts averse to the processing of each pro-drug. The same metabolic shifts observed clinically were rapidly recapitulated in leukemia cells exposed to the pro-drugs in vitro. Pyrimidine metabolism is a network that senses and preserves nucleotide balances: Decitabine, a deoxycytidine analog, and 5-azacytidine, a cytidine analog, caused acute and distinct nucleotide imbalances, by off-target inhibition of thymidylate synthase and ribonucleotide reductase respectively. Resulting expression changes in key pyrimidine metabolism enzymes peaked 72-96 hours later. Continuous pro-drug exposure stabilized metabolic shifts generated acutely, preventing DNMT1-depletion and permitting exponential leukemia out-growth as soon as day 40. Although dampening to activity of the pro-drug initially applied, adaptive metabolic responses primed for activity of the other. Hence, in xenotransplant models of chemorefractory AML, alternating decitabine with 5-azacytidine, timed to exploit compensating metabolic shifts, and addition of an inhibitor of a catabolic enzyme induced by decitabine/5-azacytidine, extended DNMT1-depletion and time-to-distress by several months versus either pro-drug alone. In sum, resistance to decitabine and 5-azacytidine emerges from adaptive responses of the pyrimidine metabolism network; these responses can be anticipated and thus exploited. GRAPHICAL ABSTRACTbiorxiv;2020.02.20.958405v1/UFIG1F1ufig1
Hamilton Betty、Zidan Asmaa M.、Hasipek Metis、Schuerger Caroline、Sobecks Ronald、Maciejewski Jaroslaw、Saunthararajah Yogen、Tomlinson Benjamin、Hsi Eric D.、Durkin Lisa、Jha Babal K.、Radivoyevitch Tomas、Hong Changjin、Carraway Hetty、Gu Xiaorong、Tohme Rita
Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland ClinicDepartment of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland ClinicDepartment of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland ClinicDepartment of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland ClinicDepartment of Hematology and Oncology, Taussig Cancer Institute, Cleveland ClinicDepartment of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic||Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland ClinicDepartment of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic||Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland ClinicDepartment of Hematology and Oncology, University HospitalsDepartment of Clinical Pathology, Tomsich Pathology Institute, Cleveland ClinicDepartment of Clinical Pathology, Tomsich Pathology Institute, Cleveland ClinicDepartment of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland ClinicDepartment of Quantitative Health Sciences, Cleveland ClinicDepartment of Quantitative Health Sciences, Cleveland ClinicDepartment of Hematology and Oncology, Taussig Cancer Institute, Cleveland ClinicDepartment of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland ClinicDepartment of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic
基础医学生物化学药学
5-azacytidinedecitabineDNMT1myelodysplastic syndromesleukemiaresistancetherapy
Hamilton Betty,Zidan Asmaa M.,Hasipek Metis,Schuerger Caroline,Sobecks Ronald,Maciejewski Jaroslaw,Saunthararajah Yogen,Tomlinson Benjamin,Hsi Eric D.,Durkin Lisa,Jha Babal K.,Radivoyevitch Tomas,Hong Changjin,Carraway Hetty,Gu Xiaorong,Tohme Rita.Resistance to decitabine and 5-azacytidine emerges from adaptive responses of the pyrimidine metabolism network[EB/OL].(2025-03-28)[2025-04-26].https://www.biorxiv.org/content/10.1101/2020.02.20.958405.点此复制
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