SAMHD1 enhances nucleoside-analogue efficacy against HIV-1 in myeloid cells

Ordonez, Paula; Kunzelmann, Simone; Groom, Harriet C. T.; Yap, Melvyn W.; Weising, Simon; Meier, Chris; Bishop, Kate N.; Taylor, Ian A.; Stoye, Jonathan P.

doi:10.1038/srep42824

Cited by 26 publications

(25 citation statements)

References 79 publications

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“…Following phosphorylation by intracellular kinases, these analogues are structurally similarly to endogenous dNTP. SAMHD1 has been shown to affect the efficacy of nucleoside analogs, either used as antiretrovirals [22][23][24][25][26] or as chemotherapeutic drugs [27][28][29]. Active SAMHD1 catalyzes the hydrolysis and inactivation of a number of different nucleoside analogues [30,31], including cytarabine (Cytosar-U ® ,Ara-C), a first line therapeutic agent for acute myelogenous leukaemia (AML) and SAMHD1 expression levels were negatively correlated with Ara-C treatment success in individuals with AML [27,29,32].…”

Section: Introductionmentioning

confidence: 99%

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

Castellví

Felip

Ezeonwumelu

et al. 2020

Cancers

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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.

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Section: Introductionmentioning

confidence: 99%

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

Castellví

Felip

Ezeonwumelu

et al. 2020

Cancers

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“…Interestingly, SAMHD1 activity has been shown to increase the efficacy of some nucleotide analogs that are not substrates of SAMHD1 (36,37). In these cases, SAMHD1 activity allows the nonsubstrate nucleotide analogs to better compete for target active sites by depleting cellular dNTPs.…”

Section: Significancementioning

confidence: 99%

The structural basis for cancer drug interactions with the catalytic and allosteric sites of SAMHD1

Knecht

Buzovetsky

Schneider

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase (dNTPase) that depletes cellular dNTPs in noncycling cells to promote genome stability and to inhibit retroviral and herpes viral replication. In addition to being substrates, cellular nucleotides also allosterically regulate SAMHD1 activity. Recently, it was shown that high expression levels of SAMHD1 are also correlated with significantly worse patient responses to nucleotide analog drugs important for treating a variety of cancers, including acute myeloid leukemia (AML). In this study, we used biochemical, structural, and cellular methods to examine the interactions of various cancer drugs with SAMHD1. We found that both the catalytic and the allosteric sites of SAMHD1 are sensitive to sugar modifications of the nucleotide analogs, with the allosteric site being significantly more restrictive. We crystallized cladribine-TP, clofarabine-TP, fludarabine-TP, vidarabine-TP, cytarabine-TP, and gemcitabine-TP in the catalytic pocket of SAMHD1. We found that all of these drugs are substrates of SAMHD1 and that the efficacy of most of these drugs is affected by SAMHD1 activity. Of the nucleotide analogs tested, only cladribine-TP with a deoxyribose sugar efficiently induced the catalytically active SAMHD1 tetramer. Together, these results establish a detailed framework for understanding the substrate specificity and allosteric activation of SAMHD1 with regard to nucleotide analogs, which can be used to improve current cancer and antiviral therapies.

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“…Studies by Arnold et al [73], Huber et al [74], and Ordonez et al [75] were the first to indicate that beyond endogenous dNTPs, triphosphates of antiviral and cytotoxic nucleoside analogues can be hydrolyzed by SAMHD1. Evolutionarily, this could hint at a role for the detoxification of exogenous nucleoside analogues as synthesized by a variety of microorganisms [76], or could simply be a byproduct of the catalytic promiscuity required by SAMHD1 for its biological role in dNTP pool homeostasis.…”

Section: Samhd1 As An Antimetabolic Resistance Factormentioning

confidence: 99%

With me or against me: Tumor suppressor and drug resistance activities of SAMHD1

Herold

Rudd

Sanjiv

et al. 2017

Experimental Hematology

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Sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1) is a (deoxy)guanosine triphosphate (dGTP/GTP)-activated deoxyribonucleoside triphosphate (dNTP) triphosphohydrolase involved in cellular dNTP homoeostasis. Mutations in SAMHD1 have been associated with the hyperinflammatory disease Aicardi-Goutières syndrome (AGS). SAMHD1 also limits cells' permissiveness to infection with diverse viruses, including human immunodeficiency virus (HIV-1), and controls endogenous retroviruses. Increasing evidence supports the role of SAMHD1 as a tumor suppressor. However, SAMHD1 also can act as a resistance factor to nucleoside-based chemotherapies by hydrolyzing their active triphosphate metabolites, thereby reducing response of various malignancies to these anticancer drugs. Hence, informed cancer therapies must take into account the ambiguous properties of SAMHD1 as both an inhibitor of uncontrolled proliferation and a resistance factor limiting the efficacy of anticancer treatments. Here, we provide evidence that SAMHD1 is a double-edged sword for patients with acute myelogenous leukemia (AML). Our time-dependent analyses of The Cancer Genome Atlas (TCGA) AML cohort indicate that high expression of SAMHD1, even though it critically limits the efficacy of high-dose ara-C therapy, might be associated with more favorable disease progression.

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SAMHD1 enhances nucleoside-analogue efficacy against HIV-1 in myeloid cells

Cited by 26 publications

References 79 publications

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

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

The structural basis for cancer drug interactions with the catalytic and allosteric sites of SAMHD1

With me or against me: Tumor suppressor and drug resistance activities of SAMHD1

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