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Erratum published on 29 June 2020, see Cancers 2020, 12(7), 1728.
Open AccessArticle

Pharmacological Modulation of SAMHD1 Activity by CDK4/6 Inhibitors Improves Anticancer Therapy

1
IrsiCaixa AIDS Research Institute, Badalona, 08916 Catalonia, Spain
2
Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain
3
Institut Català d’Oncologia, Badalona, 08916 Catalonia, Spain
4
Cienciatraducida, 08391 Barcelona, Spain
*
Author to whom correspondence should be addressed.
Theses authors contributed equally to this work.
Cancers 2020, 12(3), 713; https://doi.org/10.3390/cancers12030713
Received: 13 February 2020 / Revised: 9 March 2020 / Accepted: 16 March 2020 / Published: 18 March 2020
(This article belongs to the Special Issue Combination Therapies in Cancers)
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. View Full-Text
Keywords: SAMHD1; antimetabolite; CDK4/6; pemetrexed; HIV; cancer SAMHD1; antimetabolite; CDK4/6; pemetrexed; HIV; cancer
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Castellví, M.; Felip, E.; Ezeonwumelu, I.J.; Badia, R.; Garcia-Vidal, E.; Pujantell, M.; Gutiérrez-Chamorro, L.; Teruel, I.; Martínez-Cardús, A.; Clotet, B.; Riveira-Muñoz, E.; Margelí, M.; Esté, J.A.; Ballana, E. Pharmacological Modulation of SAMHD1 Activity by CDK4/6 Inhibitors Improves Anticancer Therapy. Cancers 2020, 12, 713.

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