Distinct Colorectal Cancer–Associated APC Mutations Dictate Response to Tankyrase Inhibition

Schatoff, Emma M.; Goswami, Sukanya; Zafra, María Paz; Foronda, Miguel; Shusterman, Michael; Leach, Benjamin I.; Katti, Alyna; Diaz, Bianca J.; Dow, Lukas E.

doi:10.1158/2159-8290.cd-19-0289

Cited by 61 publications

(74 citation statements)

References 54 publications

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“…The blockade of TNKS enzymatic activity results in the accumulation of AXIN1/2-containing β-catenin degradosomes and reduced WNT/β-catenin signaling activity [18,19]. The development of TNKS inhibitors has received focus because of their potential as a possible anticancer treatment strategy, and chemical TNKS inhibition has been shown to impact a number of tumor models [20][21][22][23].…”

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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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: 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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“…Yang and colleagues reported that Wnt/β-catenin signaling was involved in M2-like TAM polarization by regulating c-Myc, and knockdown of β-catenin in M2 TAMs suppressed the tumor-promoting functions of TAMs [39]. Although canonical Wnt/β-catenin signaling has been found to regulate M2-like TAM polarization, aberrant Wnt/β-catenin signaling in CRC, including aberrant APC and β-catenin, mainly occurs in cancer cells and affect the biological behaviors of tumor cells [40,41]. While aberrant noncanonical Wnt signaling pathway may be more likely to present in the tumor microenvironment of CRC.…”

Section: Discussionmentioning

confidence: 99%

Wnt5a/CaMKII/ERK/CCL2 axis is required for tumor-associated macrophages to promote colorectal cancer progression

et al. 2020

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Tumor-associated macrophages (TAMs) are closely correlated with tumor occurrence, invasion, and metastasis. However, factors affecting the biological functions of TAMs in colorectal cancer (CRC) are incompletely understood. Here, we found that Wnt5a was mainly expressed on TAMs of tumor stroma but not on CRC cells. Subsequently, we found that Wnt5a + TAMs facilitated tumor cell proliferation and migration, and recruited macrophages infiltration. Furthermore, Wnt5a knockdown impaired the pro-tumor roles of TAMs in vivo and in vitro. Mechanistically, the cancer-promoting roles of Wnt5a in TAMs depended on CaMKII-ERK pathway-mediated CCL2 secretion. Our data reveal the crucial role played by TAM-expressed Wnt5a in CRC tumorigenesis through paracrine secretion of CCL2. We first report the connection between Wnt5a/CaMKII/ERK/CCL2 axis and biological functions of TAMs in tumor microenvironment, indicating that Wnt5a may be a novel therapeutic target for CRC.

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“…It is postulated that G4 ligands exert anticancer effects through telomeric and non-telomeric DNA damage induction and transcriptional/ translational perturbation of cancer-related genes | 3097 SEIMIYA in xenograft models. APC loss-of-function mutations are potential predictive biomarkers of tankyrase inhibitors, 56,57 whereas β-catenin/CTNNB1 gain-of-function mutations confer the drug resistance. 58 Because Wnt/β-catenin signaling works for intestinal epithelial cells, continuous administration of tankyrase inhibitors may cause intestinal toxicity.…”

Section: Apart From Human Trf1 Tankyrase-binding Proteins Includementioning

confidence: 99%

Crossroads of telomere biology and anticancer drug discovery

Seimiya

2020

Cancer Science

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The telomere is the specialized nucleoprotein complex at the end of the chromosome. Its highly conserved 5′‐TTAGGG‐3′ repeats and shelterin protein complexes form a protective loop structure to maintain the integrity and stability of linear chromosomes. Although human somatic cells gradually shorten telomeres to undergo senescence or crisis, cancer cells activate telomerase, or the recombination‐based mechanism to maintain telomeres and exhibit immortality. As the most frequent non‐coding mutations in cancer, gain‐of‐function mutations in the promoter region of the telomerase catalytic subunit, TERT, trigger telomerase activation. Promoter methylation and copy number gain are also associated with the enhanced TERT expression. Although telomerase inhibitors were pioneered from telomere‐directed therapeutics, their efficacies are limited to cancer with short telomeres and some hematological malignancies. Other therapeutic approaches include a nucleoside analog incorporated to telomeres and TERT promoter‐driven oncolytic adenoviruses. Tankyrase poly(ADP‐ribose) polymerase, a positive regulator of telomerase, has been rediscovered as a target for Wnt‐driven cancer. Meanwhile, telomeric nucleic acids form a higher‐order structure called a G‐quadruplex (G4). G4s are formed genome‐wide and their dynamics affect various events, including replication, transcription, and translation. G4‐stabilizing compounds (G4 ligands) exert anticancer effects and are in clinical investigations. Collectively, telomere biology has provided clues for deeper understanding of cancer, which expands opportunities to discover innovative anticancer drugs.

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Distinct Colorectal Cancer–Associated APC Mutations Dictate Response to Tankyrase Inhibition

Cited by 61 publications

References 54 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

Wnt5a/CaMKII/ERK/CCL2 axis is required for tumor-associated macrophages to promote colorectal cancer progression

Crossroads of telomere biology and anticancer drug discovery

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