Tankyrase inhibition sensitizes melanoma to PD-1 immune checkpoint blockade in syngeneic mouse models

Mygland, Line; Tveita, Anders Aune; Strand, Martin Frank; Solberg, Nina; Olsen, Petter; Aizenshtadt, Aleksandra; Fauskanger, Marte; Lund, Kaja; Waaler, Jo; Lycke, Max; Dybing, Elisabeth; Nygaard, Vegard; Bøe, Sigurd Leinæs; Heintz, Karen-Marie; Hovig, Eivind; Hammarström, Clara; Corthay, Alexandre; Krauß, Stefan

doi:10.1038/s42003-020-0916-2

Cited by 27 publications

(32 citation statements)

References 69 publications

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“…We also observed that while G007-LK stabilized AMOT proteins and reduced the expression of YAP/TAZ target genes, it caused a moderate accumulation of YAP protein in the nucleus. Interestingly, in a recent publication, we showed that G007-LK treatment induces the same pattern of nuclear YAP accumulation and YAP target gene reduction in both melanoma (B16-F10) and embryonic kidney (HEK293) cell lines [27]. Through confocal imaging, we demonstrated that G007-LK treatment induced the aggregation of puncta with colocalized AMOTL1-YAP and AMOTL2-YAP.…”

Section: Discussionmentioning

confidence: 63%

“…Studies of TNKS inhibitors in cancer cells, including G007-LK [20,24], have shown that inhibiting TNKS regulates Hippo signaling [25][26][27]. The Hippo signaling pathway plays fundamental roles in tissue homeostasis and organ size control, and the pathway involves kinase cascades, adaptor proteins and the downstream oncogenes TAZ and YAP, which bind to nuclear transcription factors to activate signaling [28].…”

Section: Introductionmentioning

confidence: 99%

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A Small-Molecule Tankyrase Inhibitor Reduces Glioma Stem Cell Proliferation and Sphere Formation

Kierulf-Vieira

Sandberg

Waaler

et al. 2020

Cancers

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Evidence suggests that the growth and therapeutic resistance of glioblastoma (GBM) may be enabled by a population of glioma stem cells (GSCs) that are regulated by typical stem cell pathways, including the WNT/β-catenin signaling pathway. We wanted to explore the effect of treating GSCs with a small-molecule inhibitor of tankyrase, G007-LK, which has been shown to be a potent modulator of the WNT/β-catenin and Hippo pathways in colon cancer. Four primary GSC cultures and two primary adult neural stem cell cultures were treated with G007-LK and subsequently evaluated through the measurement of growth characteristics, as well as the expression of WNT/β-catenin and Hippo signaling pathway-related proteins and genes. Treatment with G007-LK decreased in vitro proliferation and sphere formation in all four primary GSC cultures in a dose-dependent manner. G007-LK treatment altered the expression of key downstream WNT/β-catenin and Hippo signaling pathway-related proteins and genes. Finally, cotreatment with the established GBM chemotherapeutic compound temozolomide (TMZ) led to an additive reduction in sphere formation, suggesting that WNT/β-catenin signaling may contribute to TMZ resistance. These observations suggest that tankyrase inhibition may serve as a supplement to current GBM therapy, although more work is needed to determine the exact downstream mechanisms involved.

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Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

A Small-Molecule Tankyrase Inhibitor Reduces Glioma Stem Cell Proliferation and Sphere Formation

Kierulf-Vieira

Sandberg

Waaler

et al. 2020

Cancers

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“…A very recent report indicates that inhibition of tankyrase by G007-LK can be used to overcome WNT/β-catenin-mediated resistance to immune checkpoint inhibitors [179]. While previously used tankyrase inhibitors caused bone loss [211] and intestinal toxicity [212], no such signs were observed in mice treated with G007-LK [179]. Growing evidence indicates that dietary factors along with alteration in the gutactivator protein 1 microbiota can affect WNT-signaling.…”

Section: Wnt-targeted Therapiesmentioning

confidence: 99%

WNT Signaling in Melanoma

Gajos-Michniewicz

Czyż

2020

IJMS

138

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WNT-signaling controls important cellular processes throughout embryonic development and adult life, so any deregulation of this signaling can result in a wide range of pathologies, including cancer. WNT-signaling is classified into two categories: β-catenin-dependent signaling (canonical pathway) and β-catenin-independent signaling (non-canonical pathway), the latter can be further divided into WNT/planar cell polarity (PCP) and calcium pathways. WNT ligands are considered as unique directional growth factors that contribute to both cell proliferation and polarity. Origin of cancer can be diverse and therefore tissue-specific differences can be found in WNT-signaling between cancers, including specific mutations contributing to cancer development. This review focuses on the role of the WNT-signaling pathway in melanoma. The current view on the role of WNT-signaling in cancer immunity as well as a short summary of WNT pathway-related drugs under investigation are also provided.

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“…It has been shown that TNKS1/2 inhibitors can exhibit anticancer efficacy in mouse models, either as monotherapy against colorectal cancer 8 , 24 and osteosarcoma 25 or in combination therapies together with PI3K and EGFR inhibitors against colorectal cancer 26 or with PD-1 inhibition against melanoma. 27 …”

Section: Introductionmentioning

confidence: 99%

Preclinical Lead Optimization of a 1,2,4-Triazole Based Tankyrase Inhibitor

Leenders¹,

Sowa

Waaler

et al. 2020

J. Med. Chem.

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Tankyrases 1 and 2 are central biotargets in the WNT/β-catenin signaling and Hippo signaling pathways. We have previously developed tankyrase inhibitors bearing a 1,2,4-triazole moiety and binding predominantly to the adenosine binding site of the tankyrase catalytic domain. Here we describe a systematic structure-guided lead optimization approach of these tankyrase inhibitors. The central 1,2,4-triazole template and trans- cyclobutyl linker of the lead compound 1 were left unchanged, while side-group East, West, and South moieties were altered by introducing different building blocks defined as point mutations. The systematic study provided a novel series of compounds reaching picomolar IC 50 inhibition in WNT/β - catenin signaling cellular reporter assay. The novel optimized lead 13 resolves previous atropisomerism, solubility, and Caco-2 efflux liabilities. 13 shows a favorable ADME profile, including improved Caco-2 permeability and oral bioavailability in mice, and exhibits antiproliferative efficacy in the colon cancer cell line COLO 320DM in vitro.

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Tankyrase inhibition sensitizes melanoma to PD-1 immune checkpoint blockade in syngeneic mouse models

Cited by 27 publications

References 69 publications

A Small-Molecule Tankyrase Inhibitor Reduces Glioma Stem Cell Proliferation and Sphere Formation

A Small-Molecule Tankyrase Inhibitor Reduces Glioma Stem Cell Proliferation and Sphere Formation

WNT Signaling in Melanoma

Preclinical Lead Optimization of a 1,2,4-Triazole Based Tankyrase Inhibitor

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