A Novel Tankyrase Small-Molecule Inhibitor Suppresses <i>APC</i> Mutation–Driven Colorectal Tumor Growth

Lau, Ted; Chan, Eric J.; Callow, Marinella; Waaler, Jo; Boggs, Jason; Blake, Robert A.; Magnuson, Steven; Sambrone, Amy; Schutten, Melissa M.; Firestein, Ron; Machoň, Ondřej; Kor̆ínek, Vladimír; Choo, Edna F.; Diaz, Dolores; Merchant, Mark; Polakis, Paul; Holsworth, Daniel D.; Krauß, Stefan; Costa, Mike

doi:10.1158/0008-5472.can-12-4562

Cited by 281 publications

(405 citation statements)

References 47 publications

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“…In genetic mouse models, overexpression of DKK1 or loss of TCF4 induced severe intestinal toxicity (23,24). Pharmacological Wnt inhibitors, such as Tankyrase inhibitors, also recapitulated the gut toxicity at high doses (37,39). These results are consistent with our data using a very high dose of LGK974 at 20 mg/kg per day.…”

Section: Discussionsupporting

confidence: 91%

Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974

Pan

Hsieh

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

685

620

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Wnt signaling is one of the key oncogenic pathways in multiple cancers, and targeting this pathway is an attractive therapeutic approach. However, therapeutic success has been limited because of the lack of therapeutic agents for targets in the Wnt pathway and the lack of a defined patient population that would be sensitive to a Wnt inhibitor. We developed a screen for small molecules that block Wnt secretion. This effort led to the discovery of LGK974, a potent and specific small-molecule Porcupine (PORCN) inhibitor. PORCN is a membrane-bound O-acyltransferase that is required for and dedicated to palmitoylation of Wnt ligands, a necessary step in the processing of Wnt ligand secretion. We show that LGK974 potently inhibits Wnt signaling in vitro and in vivo, including reduction of the Wnt-dependent LRP6 phosphorylation and the expression of Wnt target genes, such as AXIN2.LGK974 is potent and efficacious in multiple tumor models at well-tolerated doses in vivo, including murine and rat mechanistic breast cancer models driven by MMTV-Wnt1 and a human head and neck squamous cell carcinoma model (HN30). We also show that head and neck cancer cell lines with loss-of-function mutations in the Notch signaling pathway have a high response rate to LGK974. Together, these findings provide both a strategy and tools for targeting Wntdriven cancers through the inhibition of PORCN.Wnt inhibition | β-catenin | HNSCC

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Section: Discussionsupporting

confidence: 91%

Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974

Pan

Hsieh

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

685

620

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“…Consistent with this, tankyrase inhibitors demonstrated severe, mechanism-based GI toxicity when given orally (14). In contrast with tankyrase inhibitors, PORCN inhibitors and the recombinant Frizzled inhibitory antibodies have not shown significant toxic effects on the intestine or skin, at least in mice, at doses that effectively inhibit cancer proliferation (30,34,37).…”

Section: Potential Toxicities Of Wnt Inhibitorsmentioning

confidence: 62%

“…Tankyrase inhibitors increase AXIN abundance and therefore increase b-catenin degradation. Such drugs have been independently developed by several groups, although their oral use may be limited by mechanism-based gut toxicity (14). A more selective approach is use of small molecules to modulate b-catenin's interaction with transcriptional coactivators such as CREB-binding protein (CREBBP/ CBP).…”

Section: Downstream Wnt/b-catenin Pathway Inhibitorsmentioning

confidence: 99%

Targeting Wnts at the Source—New Mechanisms, New Biomarkers, New Drugs

Madan

Virshup

2015

Molecular Cancer Therapeutics

100

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Wnt signaling is dysregulated in many cancers and is therefore an attractive therapeutic target. The focus of drug development has recently shifted away from downstream inhibitors of b-catenin. Active inhibitors of Wnt secretion and Wnt/receptor interactions have been developed that are now entering clinical trials. Such agents include inhibitors of Wnt secretion, as well as recombinant proteins that minimize Wnt-Frizzled interactions. These new therapies arrive together with the recent insight that cancer-specific upregulation of Wnt receptors at the cell surface regulates cellular sensitivity to Wnts. Loss-of-function mutations in RNF43 or ZNRF3 and gain-of-function chromosome translocations involving RSPO2 and RSPO3 are surprisingly common and markedly increase Wnt/b-catenin signaling in response to secreted Wnts. These mutations may be predictive biomarkers to select patients responsive to newly developed upstream Wnt inhibitors.

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“…In contrast, tankyrase (TNKS) inhibitor was discovered to inhibit Wnt/b-catenin signaling, even in APC-mutated cells (16). Therefore, TNKS has been considered to be an attractive target and several TNKS inhibitors have been discovered (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

The Discovery and Characterization of K-756, a Novel Wnt/β-Catenin Pathway Inhibitor Targeting Tankyrase

Okada-Iwasaki

Takahashi

Watanabe

et al. 2016

Molecular Cancer Therapeutics

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The Wnt/b-catenin pathway is a well-known oncogenic pathway. Its suppression has long been considered as an important challenge in treating cancer patients. Among colon cancer patients in particular, most patients carry an adenomatous polyposis coli (APC) mutation that leads to an aberration of Wnt/b-catenin pathway. To discover the small molecule inhibitors of the Wnt/b-catenin pathway, we conducted highthroughput screening in APC-mutant colon cancer DLD-1 cells using a transcriptional reporter assay, which identified a selective Wnt/b-catenin pathway inhibitor, K-756. K-756 stabilizes Axin and reduces active b-catenin, and inhibits the genes downstream of endogenous Wnt/b-catenin. We subsequently identified that K-756 is a tankyrase (TNKS) inhibitor. TNKS, which belongs to the PARP family, poly-ADP ribosylates Axin and promotes Axin degradation via the proteasome pathway. K-756 binds to the induced pocket of TNKS and inhibits its enzyme activity. Moreover, PARP family enzyme assays showed that K-756 is a selective TNKS inhibitor. K-756 inhibited the cell growth of APC-mutant colorectal cancer COLO 320DM and SW403 cells by inhibiting the Wnt/b-catenin pathway. An in vivo study showed that the oral administration of K-756 inhibited the Wnt/b-catenin pathway in colon cancer xenografts in mice. To further explore the therapeutic potential of K-756, we also evaluated the effects of K-756 in non-small cell lung cancer cells. Although a single treatment of K-756 did not induce antiproliferative activity, when K-756 was combined with an EGFR inhibitor (gefitinib), it showed a strong synergistic effect. Therefore, K-756, a novel selective TNKS inhibitor, could be a leading compound in the development of anticancer agents. Mol Cancer Ther; 15(7); 1525-34. Ó2016 AACR.

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A Novel Tankyrase Small-Molecule Inhibitor Suppresses APC Mutation–Driven Colorectal Tumor Growth

Cited by 281 publications

References 47 publications

Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974

Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974

Targeting Wnts at the Source—New Mechanisms, New Biomarkers, New Drugs

The Discovery and Characterization of K-756, a Novel Wnt/β-Catenin Pathway Inhibitor Targeting Tankyrase

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