RESUMEN
Nucleobase and nucleoside analogs (NNA) are widely used as anti-viral and anti-cancer agents, and NNA phosphorylation is essential for the activity of this class of drugs. Recently, diphosphatase NUDT15 was linked to thiopurine metabolism with NUDT15 polymorphism associated with drug toxicity in patients. Profiling NNA drugs, we identify acyclovir (ACV) and ganciclovir (GCV) as two new NNAs metabolized by NUDT15. NUDT15 hydrolyzes ACV and GCV triphosphate metabolites, reducing their effects against cytomegalovirus (CMV) in vitro. Loss of NUDT15 potentiates cytotoxicity of ACV and GCV in host cells. In hematopoietic stem cell transplant patients, the risk of CMV viremia following ACV prophylaxis is associated with NUDT15 genotype (P = 0.015). Donor NUDT15 deficiency is linked to graft failure in patients receiving CMV-seropositive stem cells (P = 0.047). In conclusion, NUDT15 is an important metabolizing enzyme for ACV and GCV, and NUDT15 variation contributes to inter-patient variability in their therapeutic effects.
Asunto(s)
Aciclovir/farmacología , Antivirales/farmacología , Infecciones por Citomegalovirus/prevención & control , Ganciclovir/análogos & derivados , Pirofosfatasas/genética , Aciclovir/uso terapéutico , Adolescente , Adulto , Anciano , Animales , Profilaxis Antibiótica , Antivirales/uso terapéutico , Variación Biológica Poblacional/genética , Línea Celular , Niño , Preescolar , Cristalografía por Rayos X , Citomegalovirus/efectos de los fármacos , Citomegalovirus/genética , Citomegalovirus/aislamiento & purificación , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/etiología , Infecciones por Citomegalovirus/virología , ADN Viral/sangre , ADN Viral/aislamiento & purificación , Modelos Animales de Enfermedad , Farmacorresistencia Viral , Femenino , Ganciclovir/farmacología , Ganciclovir/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Interacciones Microbiota-Huesped/genética , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Muromegalovirus/aislamiento & purificación , Muromegalovirus/patogenicidad , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Pirofosfatasas/metabolismo , Pirofosfatasas/ultraestructura , Resultado del Tratamiento , Adulto JovenRESUMEN
Thiopurines (eg, 6-mercaptopurine [MP]) are highly efficacious antileukemic agents, but they are also associated with dose-limiting toxicities. Recent studies by us and others have identified inherited NUDT15 deficiency as a novel genetic cause of thiopurine toxicity, and there is a strong rationale for NUDT15-guided dose individualization to preemptively mitigate adverse effects of these drugs. Using CRISPR-Cas9 genome editing, we established a Nudt15-/- mouse model to evaluate the effectiveness of this strategy in vivo. Across MP dosages, Nudt15-/- mice experienced severe leukopenia, rapid weight loss, earlier death resulting from toxicity, and more bone marrow hypocellularity compared with wild-type mice. Nudt15-/- mice also showed excessive accumulation of a thiopurine active metabolite (ie, DNA-incorporated thioguanine nucleotides [DNA-TG]) in an MP dose-dependent fashion, as a plausible cause of increased toxicity. MP dose reduction effectively normalized systemic exposure to DNA-TG in Nudt15-/- mice and largely eliminated Nudt15 deficiency-mediated toxicity. In 95 children with acute lymphoblastic leukemia, MP dose adjustment also directly led to alteration in DNA-TG levels, the effects of which were proportional to the degree of NUDT15 deficiency. Using leukemia-bearing mice with concordant Nudt15 genotype in leukemia and host, we also confirmed that therapeutic efficacy was preserved in Nudt15-/- mice receiving a reduced MP dose compared with Nudt15+/+ counterparts exposed to a standard dose. In conclusion, we demonstrated that NUDT15 genotype-guided MP dose individualization can preemptively mitigate toxicity without compromising therapeutic efficacy.