MTH1 as a target to alleviate T cell driven diseases by selective suppression of activated T cells

Karsten, Stella; Fiskesund, Roland; Zhang, Xingmei; Marttila, Petra; Sanjiv, Kumar; Pham, Therese; Rasti, Azita; Bräutigam, Lars; Almlöf, Ingrid; Marcusson-Ståhl, Maritha; Sandman, Carolina; Platzack, Björn; Harris, Robert A.; Kalderén, Christina; Cederbrant, Karin; Helleday, Thomas

doi:10.1038/s41418-021-00854-4

Cited by 7 publications

(20 citation statements)

References 76 publications

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“…The correlation between ROS status and MTH1 levels was also determined, where the majority of in vitro CD3/CD28‐stimulated T cells had a higher ROS status and higher MTH1 levels than resting ones, whereas MTH1 inhibition drove the population towards an MTH1 low ROS low phenotype. This subset of T cells was not sensitive to MTH1 inhibition by TH1579 but was interestingly viable and proliferating, although not to the same extent as the MTH1 high ROS high T cells 25 . We could thus conclude that MTH1 and ROS levels correlate with each other in T cells, but they are not indispensable for all activated T cells.…”

Section: Mth1 Is Up‐regulated In Both Cancer Cells and Rapidly Dividi...mentioning

confidence: 74%

“…This subset of T cells was not sensitive to MTH1 inhibition by TH1579 but was interestingly viable and proliferating, although not to the same extent as the MTH1 high ROS high T cells. 25 We could thus conclude that MTH1 and ROS levels correlate with each other in T cells, but they are not indispensable for all activated T cells.…”

Section: Mth1 Is Up-regulated In Both Cancer Cells and Rapidly Dividi...mentioning

confidence: 80%

“…Elevated levels of phosphorylated histone H3 suggested that also the mitotic spindle was disrupted as part of the toxicity. 25 However, the mitotic effect seen in cancer cells could alternatively be due to an MTH1-independent effect by the inhibitors, as some studies have suggested regarding other MTH1 inhibitors. 28 In the context of inflammatory diseases, the elevated MTH1 levels seem to be highly specific for proinflammatory cells, as the results suggest not only a prominent gap in sensitivity between resting and activated T cells but also an increased level in psoriatic skin as compared to normal skin tissue.…”

Section: Mth1 Is Up-regulated In Both Cancer Cells and Rapidly Dividi...mentioning

confidence: 99%

“…Indeed, we showed that MTH1 inhibition induced DNA damage with increased 8‐oxoG levels and γH2AX foci in activated T cells, leading to cell cycle arrest in G2/M and apoptosis. Elevated levels of phosphorylated histone H3 suggested that also the mitotic spindle was disrupted as part of the toxicity 25 . However, the mitotic effect seen in cancer cells could alternatively be due to an MTH1‐independent effect by the inhibitors, as some studies have suggested regarding other MTH1 inhibitors 28 …”

Section: Mth1 Is Up‐regulated In Both Cancer Cells and Rapidly Dividi...mentioning

confidence: 99%

“…Figure created with BioRender.com and reprinted with permission and carefully modified from the thesis "the DNA repair enzymes MTH1 and OGG1 as targets to treat inflammation" 8 the MTH1 inhibitor TH1579 (also OXC-101 or Karonudib) selectively kills activated CD3+ T cells, without having any detectable effect on resting T cells. 8,25,26 The correlation between ROS status and MTH1 levels was also determined, where the majority of in vitro CD3/CD28-stimulated T cells had a higher ROS status and higher MTH1 levels than resting ones, whereas MTH1 inhibition drove the population towards an MTH1 low ROS low phenotype. This subset of T cells was not sensitive to MTH1 inhibition by TH1579 but was interestingly viable and proliferating, although not to the same extent as the MTH1 high ROS high T cells.…”

Section: Mth1 Is Up-regulated In Both Cancer Cells and Rapidly Dividi...mentioning

confidence: 99%

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Targeting the DNA repair enzymes MTH1 and OGG1 as a novel approach to treat inflammatory diseases

Karsten

2022

Basic Clin Pharma Tox

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Autoimmune diseases and acute inflammation like sepsis cause significant morbidity and disability globally, and new targeted therapies are urgently needed. DNA repair and reactive oxygen species (ROS) pathways have long been investigated as targets for cancer treatment, but their role in immunological research has been limited. In this MiniReview, we discuss the DNA repair enzymes MTH1 and OGG1 as targets to treat both T cell-driven diseases and acute inflammation. The MiniReview is based on a PhD thesis where both enzymes were investigated with cell and animal models. For MTH1, we found that its inhibition selectively kills activated T cells without being toxic to resting cells or other tissues. MTH1 inhibition also had an alleviating role in disease models of psoriasis and multiple sclerosis. We further identified a novel MTH1 low ROS low phenotype among activated T cells. Regarding OGG1, we demonstrated a mechanism of action of the OGG1 inhibitor TH5487, which prevents the assembly of pro-inflammatory transcription factors and mitigates acute airway infection in mouse models of pneumonia. Hence, we propose both enzymes to be promising novel targets to treat inflammation and suggest that redox and DNA repair pathways could be useful targets for future immunomodulating therapies.

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Section: Mth1 Is Up‐regulated In Both Cancer Cells and Rapidly Dividi...mentioning

confidence: 74%

Section: Mth1 Is Up-regulated In Both Cancer Cells and Rapidly Dividi...mentioning

confidence: 80%

Section: Mth1 Is Up-regulated In Both Cancer Cells and Rapidly Dividi...mentioning

confidence: 99%

Section: Mth1 Is Up‐regulated In Both Cancer Cells and Rapidly Dividi...mentioning

confidence: 99%

Section: Mth1 Is Up-regulated In Both Cancer Cells and Rapidly Dividi...mentioning

confidence: 99%

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Targeting the DNA repair enzymes MTH1 and OGG1 as a novel approach to treat inflammatory diseases

Karsten

2022

Basic Clin Pharma Tox

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

Helleday

Rudd

2022

Molecular Oncology

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The exploitation of the DNA damage response and DNA repair proficiency of cancer cells is an important anticancer strategy. The replication and repair of DNA are dependent upon the supply of deoxynucleoside triphosphate (dNTP) building blocks, which are produced and maintained by nucleotide metabolic pathways. Enzymes within these pathways can be promising targets to selectively induce toxic DNA lesions in cancer cells. These same pathways also activate antimetabolites, an important group of chemotherapies that disrupt both nucleotide and DNA metabolism to induce DNA damage in cancer cells. Thus, dNTP metabolic enzymes can also be targeted to refine the use of these chemotherapeutics, many of which remain standard of care in common cancers. In this review article, we will discuss both these approaches exemplified by the enzymes MTH1, MTHFD2 and SAMHD1.

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Mitotic MTH1 Inhibitors in Treatment of Cancer

Helleday

2023

Cancer Treatment and Research

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MTH1 as a target to alleviate T cell driven diseases by selective suppression of activated T cells

Cited by 7 publications

References 76 publications

Targeting the DNA repair enzymes MTH1 and OGG1 as a novel approach to treat inflammatory diseases

Targeting the DNA repair enzymes MTH1 and OGG1 as a novel approach to treat inflammatory diseases

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

Mitotic MTH1 Inhibitors in Treatment of Cancer

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