Validation and development of MTH1 inhibitors for treatment of cancer

Berglund, Ulrika Warpman; Sanjiv, Kumar; Gad, Helge; Kalderén, Christina; Koolmeister, Tobias; Pham, T. M.; Göktürk, Camilla; Jafari, Rozbeh; Maddalo, Gianluca; Seashore‐Ludlow, Brinton; Chernobrovkin, Alexey; Manoilov, Aleksandr; Pateras, Ioannis S.; Rasti, Azita; Jemth, Ann-Sofie; Almlöf, Ingrid; Loseva, Olga; Visnes, Torkild; Einarsdottir, Berglind O.; Gaugaz, Fabienne Z.; Saleh, Aljona; Platzack, Björn; Wallner, Olov; Vallin, Karl S. A.; Henriksson, Martin; Wakchaure, Prasad B.; Borhade, Sanjay R.; Herr, Patrick; Kallberg, Yvonne; Baranczewski, Paweł; Homan, Evert; Wiita, Elisée; Nagpal, Varun; Meijer, Thomas; Schipper, Nicolaas; Rudd, Sean G.; Bräutigam, Lars; Lindqvist, Anna-Karin; Filppula, Anne M.; Lee, Te‐Chang; Artursson, Per; Nilsson, Jonas A.; Gorgoulis, Vassilis G.; Lehtiö, Janne; Zubarev, Roman A.; Scobie, Martin; Helleday, Thomas

doi:10.1093/annonc/mdw429

Cited by 114 publications

(120 citation statements)

References 20 publications

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“…Similar effects of TH588 regarding cellular survival were shown recently [15, 25, 28]. Our results show a potent induction of apoptotic cell death mechanisms upon TH588 treatment (Fig 2).…”

Section: Discussionsupporting

confidence: 91%

The MTH1 inhibitor TH588 demonstrates anti-tumoral effects alone and in combination with everolimus, 5-FU and gamma-irradiation in neuroendocrine tumor cells

et al. 2017

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Modulation of the redox system in cancer cells has been considered a promising target for anti-cancer therapy. The novel MTH1 inhibitor TH588 proved tremendous potential in terms of cancer cell eradication, yet its specificity has been questioned by recent reports, indicating that TH588 may also induce cancer cell death by alternative mechanisms than MTH1 inhibition. Here we used a panel of heterogeneous neuroendocrine tumor cells in order to assess cellular mechanisms and molecular signaling pathways implicated in the effects of TH588 alone as well as dual-targeting approaches combining TH588 with everolimus, cytotoxic 5-fluorouracil or γ-irradiation. Our results reflect that TH588 alone efficiently decreased the survival of neuroendocrine cancer cells by PI3K-Akt-mTOR axis downregulation, increased apoptosis and oxidative stress. However, in the dual-targeting approaches cell survival was further decreased due to an even stronger downregulation of the PI3K-Akt-mTOR axis and augmentation of apoptosis but not oxidative stress. Furthermore, we could attribute TH588 chemo- and radio-sensitizing properties. Collectively our data not only provide insights into how TH588 exactly kills cancer cells but also depict novel perspectives for combinatorial treatment approaches encompassing TH588.

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“…Similar effects of TH588 regarding cellular survival were shown recently [15, 25, 28]. Our results show a potent induction of apoptotic cell death mechanisms upon TH588 treatment (Fig 2).…”

Section: Discussionsupporting

confidence: 91%

The MTH1 inhibitor TH588 demonstrates anti-tumoral effects alone and in combination with everolimus, 5-FU and gamma-irradiation in neuroendocrine tumor cells

et al. 2017

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“…Finally, we note that a key difference between the studies that show a tumor-suppressive effect of MTH1 inhibition (including ours) [27,35,36,42] and those that do not [37,38,39] is that the former studies explicitly test effects of MTH1 inhibition in in vivo tumor formation models, whereas the latter solely utilize in vitro models (see Table 1). We have shown that a fairly modest in vitro proliferative defect (particularly in p53-nonfunctional cell lines, which many of the conflicting studies utilize) can manifest as a strong defect in in vivo tumor formation [27].…”

Section: Molecular and Cellular Contexts Underlying The Outcomes Omentioning

confidence: 99%

“…Recently, Helleday and colleagues published their best-in-class inhibitor, TH1579, which was able to reduce viability in a number of cell lines, concomitantly elevating p53 and DNA DSB markers [42]. In this comprehensive study, Warpman et al examined the selectivity profile of TH1579 against 87 other proteins besides MTH1, including kinases and base excision repair proteins.…”

Section: Outcomes Of Mth1 Inhibitors In Different Cancer Modelsmentioning

confidence: 99%

“…Warpman et al [42] also carried out proteomic profiling of their inhibitors, to compare their results against those of Kawamura et al [37] However, they found their compounds clustered with nutrient starvation rather than microtubule inhibitors as reported by Kawamura et al [37]. The source of this inconsistency between the two studies could be due to the different cell lines (HeLa [37] vs. HCT116 [42]), drug doses and time points (TH287 at 3 µM for 18 h [37] vs. TH588 at 5 µM for 72 h [42]) and, potentially, the actual methods used for proteomic profiling.…”

Section: Outcomes Of Mth1 Inhibitors In Different Cancer Modelsmentioning

confidence: 99%

“…The source of this inconsistency between the two studies could be due to the different cell lines (HeLa [37] vs. HCT116 [42]), drug doses and time points (TH287 at 3 µM for 18 h [37] vs. TH588 at 5 µM for 72 h [42]) and, potentially, the actual methods used for proteomic profiling. Finally, Warpman et al reported that, unlike TH588, several of the MTH1 inhibitors that did not induce cytotoxicity [38,39] also did not elevate 8-oxo-dGTP incorporation into genomic DNA, a critical factor in order for MTH1 inhibition to induce DNA breaks and tumor suppressor responses [30].…”

Section: Outcomes Of Mth1 Inhibitors In Different Cancer Modelsmentioning

confidence: 99%

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MTH1 as a Chemotherapeutic Target: The Elephant in the Room

Samaranayake

Huynh

Rai

2017

Cancers

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Many tumors sustain elevated levels of reactive oxygen species (ROS), which drive oncogenic signaling. However, ROS can also trigger anti-tumor responses, such as cell death or senescence, through induction of oxidative stress and concomitant DNA damage. To circumvent the adverse consequences of elevated ROS levels, many tumors develop adaptive responses, such as enhanced redox-protective or oxidatively-generated damage repair pathways. Targeting these enhanced oxidative stress-protective mechanisms is likely to be both therapeutically effective and highly specific to cancer, as normal cells are less reliant on such mechanisms. In this review, we discuss one such stress-protective protein human MutT Homolog1 (MTH1), an enzyme that eliminates 8-oxo-7,8-dihydro-2’-deoxyguanosine triphosphate (8-oxodGTP) through its pyrophosphatase activity, and is found to be elevated in many cancers. Our studies, and subsequently those of others, identified MTH1 inhibition as an effective tumor-suppressive strategy. However, recent studies with the first wave of MTH1 inhibitors have produced conflicting results regarding their cytotoxicity in cancer cells and have led to questions regarding the validity of MTH1 as a chemotherapeutic target. To address the proverbial "elephant in the room" as to whether MTH1 is a bona fide chemotherapeutic target, we provide an overview of MTH1 function in the context of tumor biology, summarize the current literature on MTH1 inhibitors, and discuss the molecular contexts likely required for its efficacy as a therapeutic target.

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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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Validation and development of MTH1 inhibitors for treatment of cancer

Abstract: We demonstrate that in order to kill cancer cells MTH1 inhibitors must also introduce oxidized nucleotides into DNA. Furthermore, we describe TH1579 as a best-in-class MTH1 inhibitor, which we expect to be useful in order to further validate the MTH1 inhibitor concept.

Cited by 114 publications

References 20 publications

The MTH1 inhibitor TH588 demonstrates anti-tumoral effects alone and in combination with everolimus, 5-FU and gamma-irradiation in neuroendocrine tumor cells

The MTH1 inhibitor TH588 demonstrates anti-tumoral effects alone and in combination with everolimus, 5-FU and gamma-irradiation in neuroendocrine tumor cells

MTH1 as a Chemotherapeutic Target: The Elephant in the Room

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

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