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

Herold, Nikolas; Rudd, Sean G.; Sanjiv, Kumar; Kutzner, Juliane; Myrberg, Ida Hed; Paulin, Cynthia B.J.; Olsen, Thale Kristin; Helleday, Thomas; Henter, Jan‐Inge; Schaller, Torsten

doi:10.1016/j.exphem.2017.05.001

Cited by 42 publications

(57 citation statements)

References 85 publications

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“…Attempts to predict the effect of SAMHD1 on drug efficacy based on the specific base targeted or chemical structure did not show any clear correlation, although purine nucleoside analogues may be more prone to gain activity in SAMHD1-depleted cells. Based on previous data showing that beyond endogenous dNTPs, triphosphorylated nucleoside analogues can be hydrolyzed by SAMHD1 [28][29][30]35] and considering that recombinant SAMHD1 exhibits Ara-CTPase activity in vitro [29], we hypothesized that compounds whose activity is enhanced in the absence of SAMHD1 are enzyme substrates. On the contrary, and as previously demonstrated for NRTI [23][24][25], compounds that lose activity in the absence of SAMHD1 would be competing with the intracellular dNTP pool, which is lower when SAMHD1 is active.…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…The interpatient susceptibility to high‐dose ara‐C regimens is linked to the propensity of AML blasts to accumulate the active triphosphate metabolite ara‐CTP (Plunkett et al , ), which causes DNA damage by perturbing DNA synthesis (Tsesmetzis et al , ). A main determinant for ara‐CTP exposure, and thus a key factor for ara‐C efficacy, is the deoxynucleoside triphosphate (dNTP) triphosphohydrolase SAM and HD domain‐containing protein‐1 (SAMHD1), which we and others identified as an ara‐CTPase (Schneider et al , ; Herold et al , ,b,c; Hollenbaugh et al , ; Rudd et al , ; Rassidakis et al , ). Accordingly, inactivation of SAMHD1 is a prime goal for rational improvement of ara‐C‐based therapies; however, no valid clinical strategies exist, nor are known efforts under development ().…”

Section: Introductionmentioning

confidence: 75%

“…Generation of THP-1 and HL-60/iva SAMHD1 +/+ and SAMHD1 À/À cell clones was described previously (Herold et al, 2017b), referred to as THP-1 ctrl, THP-1 g2-2, HL-60/iva g2-3 and HL-60/iva g2-2, respectively (Herold et al, 2017b). Generation of firefly luciferaseexpressing THP-1 SAMHD1 +/+ and SAMHD1 À/À cell clones has been described (Herold et al, 2017c). Firefly luciferase-expressing HL-60 SAMHD1 +/+ and SAMHD1 À/À cells were generated similarly by transducing HL-60 SAMHD1 +/+ clone g2-3 and SAMHD1 À/À clone g2-2, respectively, with VSV-G pseudotyped lentiviral vector expressing HA-LUC (pCSXW-HALUC), previously described (Herold et al, 2017c).…”

Section: Generation Of Samhd1 Crispr/cas9 Cell Linesmentioning

confidence: 99%

Ribonucleotide reductase inhibitors suppress SAMHD 1 ara‐ CTP ase activity enhancing cytarabine efficacy

et al. 2020

Self Cite

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The deoxycytidine analogue cytarabine (ara‐C) remains the backbone treatment of acute myeloid leukaemia (AML) as well as other haematological and lymphoid malignancies, but must be combined with other chemotherapeutics to achieve cure. Yet, the underlying mechanism dictating synergistic efficacy of combination chemotherapy remains largely unknown. The dNTPase SAMHD1, which regulates dNTP homoeostasis antagonistically to ribonucleotide reductase (RNR), limits ara‐C efficacy by hydrolysing the active triphosphate metabolite ara‐CTP. Here, we report that clinically used inhibitors of RNR, such as gemcitabine and hydroxyurea, overcome the SAMHD1‐mediated barrier to ara‐C efficacy in primary blasts and mouse models of AML, displaying SAMHD1‐dependent synergy with ara‐C. We present evidence that this is mediated by dNTP pool imbalances leading to allosteric reduction of SAMHD1 ara‐CTPase activity. Thus, SAMHD1 constitutes a novel biomarker for combination therapies of ara‐C and RNR inhibitors with immediate consequences for clinical practice to improve treatment of AML.

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“…SAMHD1 has been described as a negative biomarker in AML treatment because of its ability to interfere with the therapeutic activity of several drugs [18,52,53]. On the other hand, a positive correlation between SAMHD1 mRNA expression and long-term AML prognosis has been reported [54]. Furthermore, our recent study demonstrated that endogenous SAMHD1 protein levels are highly variable in peripheral blood mononuclear cells from 22 different AML patients, likely due to genetic heterogeneity of AML patients.…”

Section: Discussionmentioning

confidence: 72%

SAMHD1 inhibits epithelial cell transformation in vitro and affects leukemia development in xenograft mice

Kodigepalli

Bonifati

et al. 2018

Cell Cycle

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Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a mammalian dNTP hydrolase (dNTPase) and functions as a negative regulator in the efficacy of cytarabine treatment of acute myeloid leukemia (AML). We have reported that SAMHD1 knockout (KO) increased the activity of phosphoinositide 3-kinase (PI3K) in AML-derived THP-1 cells and attenuated their ability to form subcutaneous tumors in xenografted immunodeficient mice. However, the functional significance of SAMHD1 in controlling AML leukemogenesis remains unclear. Previous studies show that in vitro transformation of Madin-Darby canine kidney (MDCK) epithelial cells by the Jaagsiekte sheep retrovirus (JSRV) envelope protein requires activation of the PI3K/Akt oncogenic signaling pathway. Using this cell transformation model, we demonstrated that ectopic expression of wild-type human SAMHD1 or a dNTPase-defective SAMHD1 mutant (HD/AA) significantly inhibited MDCK cell transformation, but did not affect cell proliferation. To visualize and quantify THP-1 cell growth and metastasis in xenografted immunodeficient mice, we generated luciferase-expressing stable SAMHD1 KO THP-1 cells and control THP-1 cells, which were injected intravenously into immunodeficient mice. Bioluminescence imaging and quantification analysis of xenografted mice revealed that SAMHD1 KO cell-derived tumors had similar growth and metastatic potential compared with control cells at 35 days post-injection. However, mice xenografted with SAMHD1 KO cells showed greater survival compared with mice injected with control cells. Our data suggest that exogenous SAMHD1 expression suppresses in vitro cell transformation independently of its dNTPase activity, and that endogenous SAMHD1 affects AML tumorigenicity and disease progression in vivo.

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

Cited by 42 publications

References 85 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

Ribonucleotide reductase inhibitors suppress SAMHD 1 ara‐ CTP ase activity enhancing cytarabine efficacy

SAMHD1 inhibits epithelial cell transformation in vitro and affects leukemia development in xenograft mice

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