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

Marc Castellví,José Esté,Roger Badia,Eva Riveira-Muñoz,Bonaventura Clotet,Lucía Gutiérrez-Chamorro,Ifeanyi Ezeonwumelu,Edurne Garcia-Vidal,Iris Teruel,Anna Martínez-Cardús,Ester Ballana,Mireia Margelí,Eudald Felip,Maria Pujantell

doi:10.3390/cancers12030713

Abstract

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.

Highlights

Sterile alpha motif and histidine-aspartic acid domain-containing protein 1 (SAMHD1) is a deoxynucleotide triphosphate hydrolase [1]
SAMHD1 function is inhibited by phosphorylation, a process controlled by cyclin-dependent kinases (CDK) and tightly regulated during cell cycle progression [13,14,15]
Primary monocyte-derived macrophages (MDMs) are susceptible to HIV-1 infection, and its replication capacity is dependent on SAMHD1 expression

Summary

Introduction

Sterile alpha motif and histidine-aspartic acid domain-containing protein 1 (SAMHD1) is a deoxynucleotide triphosphate hydrolase [1]. Through its dNTPase activity, SAMHD1 maintains the intracellular dNTP pool at levels adequate for DNA replication and repair but below a potentially mutagenic threshold [2]. Aicardi–Goutieres syndrome (AGS), a severe autoimmune disease [3], but later it was proposed as a tumor suppressor gene, since mutations in SAMHD1 are associated with different types of cancer [4,5]. SAMHD1 acts as a viral restriction factor, limiting the permissiveness of cells to diverse viruses (reviewed in [9]), including human immunodeficiency virus (HIV-1) [10,11]. SAMHD1 inhibits retroviral replication at the reverse transcription (RT) step by maintaining the intracellular concentration of dNTP below the threshold required for reverse transcription of the viral RNA genome into DNA [10,11]. Different pharmacological agents have been shown to block SAMHD1 phosphorylation, inducing SAMHD1 function and viral restriction [16,17,18,19,20]

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Discussion

Conclusion