Targeting the DNA damage response and repair in cancer through nucleotide metabolism

Helleday, Thomas; Rudd, Sean G.

doi:10.1002/1878-0261.13227

Cited by 23 publications

(13 citation statements)

References 215 publications

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“…SAMHD1 has multifaceted roles important to human health and disease, through its enzymatic activity as a central dNTPase and through its non-catalytic activities 2 . More recently, we and others have reported that SAMHD1 can also deactivate antileukemic drugs, notably cytarabine, the backbone therapy for AML, and thereby limit anticancer efficacy 39,40,50 .…”

Section: Discussionmentioning

confidence: 99%

“…Sterile alpha motif and histidine-aspartic acid domain containing protein-1 (SAMHD1) is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase with critical roles in human health and disease 1,2 . Belonging to the HD-domain superfamily, a group of metal-dependent phosphohydrolases 3 , SAMHD1 catalyses the hydrolysis of canonical dNTPs producing the cognate deoxynucleoside and inorganic triphosphate 4,5 .…”

Section: Introductionmentioning

confidence: 99%

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Identification and evaluation of small-molecule inhibitors against the dNTPase SAMHD1viaa comprehensive screening funnel

Zhang

Paulin

Michel

et al. 2023

Preprint

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Sterile alpha motif and histidine-aspartic acid domain containing protein-1 (SAMHD1) is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase central to cellular nucleotide pool homeostasis. Recent literature has also demonstrated how SAMHD1 can detoxify chemotherapy metabolites thereby controlling their clinical responses. To further understand SAMHD1 biology and to investigate the potential of targeting this enzyme as a neoadjuvant to existing chemotherapies we set out to discover selective small molecule-based inhibitors of SAMHD1. Here we report a discovery pipeline encompassing a biochemical screening campaign and a set of complementary biochemical, biophysical, and cell-based readouts for further characterisation of the screen output. The identified hit compound TH6342 and its analogues, accompanied by their inactive negative control analogue TH7126, demonstrated specific, low μM potency in inhibiting the hydrolysis of both natural substrates and nucleotide analogue therapeutics, shown using complementary enzyme-coupled and direct enzymatic activity assays. Their mode of inhibition was subsequently detailed by coupling kinetic studies with thermal shift assays, where TH6342 and analogues were shown to engage with pre-tetrameric SAMHD1 and deter the oligomerisation and allosteric activation of SAMHD1 without occupying nucleotide binding pockets. We further outline the development and application of multiple cellular assays for assessing cellular target engagement and associated functional effects, including CETSA and an in-cell dNTP hydrolase activity assay, which highlighted future optimisation strategies of this chemotype. In summary, with a novel mode of inhibition, TH6342 and analogues broaden the set of tool compounds available in deciphering SAMHD1 enzymology and functions, and furthermore, the discovery pipeline reported herein represents a thorough framework for future SAMHD1 inhibitor development.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification and evaluation of small-molecule inhibitors against the dNTPase SAMHD1viaa comprehensive screening funnel

Zhang

Paulin

Michel

et al. 2023

Preprint

Self Cite

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“…Mutations induced by GI were increased within the TME compared to cells under standard culture conditions, and hypoxic conditions also contributed to mutagenesis ( Bindra and Glazer, 2005 ), suggesting the TME can be an indispensable inducer of GI in cancer cells ( Chan et al, 2009 ; Bizzarri and Cucina, 2014 ; Sonugur and Akbulut, 2019 ). It was convinced that hypoxia is a major factor leading to GI, and increased reactive oxygen species can induce single- and double-strand DNA breaks which promote the translocations, deletions, and amplifications in tumor cells ( Degtyareva et al, 2013 ; Helleday and Rudd, 2022 ). This might indicate the possibility of GI-based signature having implications in reflecting the TME and determining treatment, while current evidence is relatively limited.…”

Section: Introductionmentioning

confidence: 99%

Characterization of tumor immune microenvironment and cancer therapy for head and neck squamous cell carcinoma through identification of a genomic instability-related lncRNA prognostic signature

Jing

2022

Front. Genet.

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Head and neck squamous cell carcinoma (HNSCC) represents one of the most prevalent and malignant tumors of epithelial origins with unfavorable outcomes. Increasing evidence has shown that dysregulated long non-coding RNAs (lncRNAs) correlate with tumorigenesis and genomic instability (GI), while the roles of GI-related lncRNAs in the tumor immune microenvironment (TIME) and predicting cancer therapy are still yet to be clarified. In this study, transcriptome and somatic mutation profiles with clinical parameters were obtained from the TCGA database. Patients were classified into GI-like and genomic stable (GS)-like groups according to the top 25% and bottom 25% cumulative counts of somatic mutations. Differentially expressed lncRNAs (DElncRNAs) between GI- and GS-like groups were identified as GI-related lncRNAs. These lncRNA-related coding genes were enriched in cancer-related KEGG pathways. Patients totaling 499 with clinical information were randomly divided into the training and validation sets. A total of 18 DElncRNAs screened by univariate Cox regression analysis were associated with overall survival (OS) in the training set. A GI-related lncRNA signature that comprised 10 DElncRNAs was generated through least absolute shrinkage and selection operator (Lasso)-Cox regression analysis. Patients in the high-risk group have significantly decreased OS vs. patients in the low-risk group, which was verified in internal validation and entire HNSCC sets. Integrated HNSCC sets from GEO confirmed the notable survival stratification of the signature. The time-dependent receiver operating characteristic curve demonstrated that the signature was reliable. In addition, the signature retained a strong performance of OS prediction for patients with various clinicopathological features. Cell composition analysis showed high anti-tumor immunity in the low-risk group which was evidenced by increased infiltrating CD8+ T cells and natural killer cells and reduced cancer-associated fibroblasts, which was convinced by immune signatures analysis via ssGSEA algorithm. T helper/IFNγ signaling, co-stimulatory, and co-inhibitory signatures showed increased expression in the low-risk group. Low-risk patients were predicted to be beneficial to immunotherapy, which was confirmed by patients with progressive disease who had high risk scores vs. complete remission patients. Furthermore, the drugs that might be sensitive to HNSCC were identified. In summary, the novel prognostic GILncRNA signature provided a promising approach for characterizing the TIME and predicting therapeutic strategies for HNSCC patients.

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“…One-carbon (1C) metabolism is central to the supply of nucleotides for DNA synthesis and repair. Without sufficient nucleotide supply to meet the proliferative demands, cells undergo cell cycle arrest or cell death due to replication stress and genomic instability [1][2][3] . Enzymes involved in the 1C metabolism pathway are commonly upregulated in cancer to produce nucleotides and amino acids required for rapid proliferation [4][5][6] .…”

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confidence: 99%

Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells

et al. 2023

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Cancer cells fuel their increased need for nucleotide supply by upregulating one-carbon (1C) metabolism, including the enzymes methylenetetrahydrofolate dehydrogenase–cyclohydrolase 1 and 2 (MTHFD1 and MTHFD2). TH9619 is a potent inhibitor of dehydrogenase and cyclohydrolase activities in both MTHFD1 and MTHFD2, and selectively kills cancer cells. Here, we reveal that, in cells, TH9619 targets nuclear MTHFD2 but does not inhibit mitochondrial MTHFD2. Hence, overflow of formate from mitochondria continues in the presence of TH9619. TH9619 inhibits the activity of MTHFD1 occurring downstream of mitochondrial formate release, leading to the accumulation of 10-formyl-tetrahydrofolate, which we term a ‘folate trap’. This results in thymidylate depletion and death of MTHFD2-expressing cancer cells. This previously uncharacterized folate trapping mechanism is exacerbated by physiological hypoxanthine levels that block the de novo purine synthesis pathway, and additionally prevent 10-formyl-tetrahydrofolate consumption for purine synthesis. The folate trapping mechanism described here for TH9619 differs from other MTHFD1/2 inhibitors and antifolates. Thus, our findings uncover an approach to attack cancer and reveal a regulatory mechanism in 1C metabolism.

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Targeting the DNA damage response and repair in cancer through nucleotide metabolism

Cited by 23 publications

References 215 publications

Identification and evaluation of small-molecule inhibitors against the dNTPase SAMHD1viaa comprehensive screening funnel

Identification and evaluation of small-molecule inhibitors against the dNTPase SAMHD1viaa comprehensive screening funnel

Characterization of tumor immune microenvironment and cancer therapy for head and neck squamous cell carcinoma through identification of a genomic instability-related lncRNA prognostic signature

Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells

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