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Pharmacological modulation of SAMHD1 activity by CDK4/6 inhibitors improves anticancer therapy
Castellví, Marc (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Felip, Eudald (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Ezeonwumelu, Ifeanyi Jude (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Badia, Roger (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Garcia-Vidal, Edurne (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Pujantell, Maria (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Gutiérrez-Chamorro, Lucía (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Teruel, Iris (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Martínez Cardús, Anna (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Clotet, Bonaventura (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Riveira-Muñoz, Eva (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Margelí, Mireia (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Ballana, Ester (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Universitat Autònoma de Barcelona

Fecha: 2020
Resumen: Sterile alpha motif and histidine-aspartic acid domain-containing protein 1 (SAMHD1) is a dNTP triphosphohydrolase involved in the regulation of the intracellular dNTP pool, linked to viral restriction, cancer development and autoimmune disorders. SAMHD1 function is regulated by phosphorylation through a mechanism controlled by cyclin-dependent kinases and tightly linked to cell cycle progression. Recently, SAMHD1 has been shown to decrease the efficacy of nucleotide analogs used as chemotherapeutic drugs. Here, we demonstrate that SAMHD1 can enhance or decrease the efficacy of various classes of anticancer drug, including nucleotide analogues, but also anti-folate drugs and CDK inhibitors. Importantly, we show that selective CDK4/6 inhibitors are pharmacological activators of SAMHD1 that act by inhibiting its inactivation by phosphorylation. Combinations of a CDK4/6 inhibitor with nucleoside or folate antimetabolites potently enhanced drug efficacy, resulting in highly synergic drug combinations (CI < 0. 04). Mechanistic analyses reveal that cell cycle-controlled modulation of SAMHD1 function is the central process explaining changes in anticancer drug efficacy, therefore providing functional proof of the potential of CDK4/6 inhibitors as a new class of adjuvants to boost chemotherapeutic regimens. The evaluation of SAMHD1 expression in cancer tissues allowed for the identification of cancer types that would benefit from the pharmacological modulation of SAMHD1 function. In conclusion, these results indicate that the modulation of SAMHD1 function may represent a promising strategy for the improvement of current antimetabolite-based treatments.
Nota: Funding: This research was funded by Instituto de Salud Carlos III, Fondo de Investigación Sanitaria (FIS) PI16/00103, PI17/00624 and CP14/00016 cofinanced by FEDER. EB is a research fellow from ISCIII-FIS (CP14/00016). EGV, MP, LG are research fellows from Generalitat de Catalunya AGAUR. RB is a research fellow from PERIS, Generalitat de Catalunya (PERIS SLT002/16/00059). IE is a research fellow from la Caixa Bank Foundation (LCF/BQ/IN18/11660017) cofunded by the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 713673.
Nota: Número d'acord de subvenció EC/Marie Sklodowska-Curie/713673
Nota: Número d'acord de subvenció Caixa Bank Foundation/LCF/BQ/IN18/11660017
Nota: Número d'acord de subvenció ISCIII/FIS/CP14/00016
Nota: Número d'acord de subvenció ISCIII/FIS/PI17/00624
Nota: Número d'acord de subvenció ISCIII/FIS/PI16/00103
Nota: Número d'acord de subvenció AGAUR/PERIS/SLT002/16/00059
Derechos: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Lengua: Anglès
Documento: article ; recerca ; publishedVersion
Publicado en: Cancers, Vol. 12 Núm. 3 (march 2020) , p. 713, ISSN 2072-6694

DOI: 10.3390/cancers12030713
PMID: 32197329


19 p, 2.6 MB

El registro aparece en las colecciones:
Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Artículos > Artículos de investigación
Artículos > Artículos publicados

 Registro creado el 2020-04-15, última modificación el 2020-08-10



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