Tankyrase-targeted therapeutics: expanding opportunities in the PARP family

Riffell, Jenna L.; Lord, Christopher J.; Ashworth, Alan

doi:10.1038/nrd3868

Cited by 248 publications

(258 citation statements)

References 105 publications

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“…This is the first Wnt/b-catenin pathway inhibitor tested in clinical trials (NCT01351103), which blocks porcupine activity and the maturation of Wnt ligands upstream in the oncogenic signaling. As tankyrases parsylate and commit other proteins to degradation in addition to AXIN1 and 2 (40,41), it could be of interest to evaluate to what extent the antitumoral capacity of tankyrase inhibitors rely on affecting any other cell processes beyond Wnt/b-catenin signaling.…”

Section: Discussionmentioning

confidence: 99%

Tankyrase Inhibition Blocks Wnt/β-Catenin Pathway and Reverts Resistance to PI3K and AKT Inhibitors in the Treatment of Colorectal Cancer

Arqués

Chicote

Puig

et al. 2016

Clinical Cancer Research

154

125

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Purpose: Oncogenic mutations in the KRAS/PI3K/AKT pathway are one of the most frequent alterations in cancer. Although PI3K or AKT inhibitors show promising results in clinical trials, drug resistance frequently emerges. We previously revealed Wnt/b-catenin signaling hyperactivation as responsible for such resistance in colorectal cancer. Here we investigate Wnt-mediated resistance in patients treated with PI3K or AKT inhibitors in clinical trials and evaluate the efficacy of a new Wnt/tankyrase inhibitor, NVP-TNKS656, to overcome such resistance.Experimental Design: Colorectal cancer patient-derived sphere cultures and mouse tumor xenografts were treated with NVP-TNKS656, in combination with PI3K or AKT inhibitors.We analyzed progression-free survival of patients treated with different PI3K/AKT/mTOR inhibitors in correlation with Wnt/b-catenin pathway activation, oncogenic mutations, clinicopathological traits, and gene expression patterns in 40 colorectal cancer baseline tumors.Results: Combination with NVP-TNKS656 promoted apoptosis in PI3K or AKT inhibitor-resistant cells with high nuclear b-catenin content. High FOXO3A activity conferred sensitivity to NVP-TNKS656 treatment. Thirteen of 40 patients presented high nuclear b-catenin content and progressed earlier upon PI3K/AKT/ mTOR inhibition. Nuclear b-catenin levels predicted drug response, whereas clinicopathologic traits, gene expression profiles, or frequent mutations (KRAS, TP53, or PIK3CA) did not.Conclusions: High nuclear b-catenin content independently predicts resistance to PI3K and AKT inhibitors. Combined treatment with a Wnt/tankyrase inhibitor reduces nuclear b-catenin, reverts such resistance, and represses tumor growth. FOXO3A content and activity predicts response to Wnt/b-catenin inhibition and together with b-catenin may be predictive biomarkers of drug response providing a rationale to stratify colorectal cancer patients to be treated with PI3K/AKT/mTOR and Wnt/b-catenin inhibitors.

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Section: Discussionmentioning

confidence: 99%

Tankyrase Inhibition Blocks Wnt/β-Catenin Pathway and Reverts Resistance to PI3K and AKT Inhibitors in the Treatment of Colorectal Cancer

Arqués

Chicote

Puig

et al. 2016

Clinical Cancer Research

154

125

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“…Tankyrase was originally discovered as a regulator of telomere maintenance in mediating PARsylation of telomeric repeatbinding factor 1 (TRF1) to control its binding to telomeric DNA (Smith et al 1998;Riffell et al 2012). In the Wnt/β-catenin pathway, tankyrase PARsylates Axin, which in turn promotes its ubiquitination by the ubiquitin E3 ligase RNF146 and the subsequent proteasomal degradation (Huang et al 2009;Callow et al 2011;Zhang et al 2011).…”

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confidence: 99%

USP25 regulates Wnt signaling by controlling the stability of tankyrases

Liu

et al. 2017

Genes Dev.

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Aberrant activation of the Wnt signaling pathway plays an important role in human cancer development. Wnt signaling is negatively regulated by Axin, a scaffolding protein that controls a rate-limiting step in the destruction of β-catenin, the central activator of the Wnt pathway. In Wnt-stimulated cells, Axin is rapidly modified by tankyrasemediated poly(ADP-ribosyl)ation, which promotes the proteolysis of Axin and consequent stabilization of β-catenin. Thus, regulation of the levels and activity of tankyrases is mechanistically important in controlling Wnt signaling. Here, we identify ubiquitin-specific protease 25 (USP25) as a positive regulator of Wnt/β-catenin signaling. We found that USP25 directly interacted with tankyrases to promote their deubiquitination and stabilization. We demonstrated that USP25 deficiency could promote the degradation of tankyrases and consequent stabilization of Axin to antagonize Wnt signaling. We further characterized the interaction between TNKS1 and USP25 by X-ray crystal structure determination. Our results provide important new insights into the molecular mechanism that regulates the turnover of tankyrases and the possibility of targeting the stability of tankyrases by antagonizing their interaction with USP25 to modulate the Wnt/β-catenin pathway.

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“…Since the discovery of Wnt/b-catenin pathway regulation by TNKS, the development of TNKS inhibitors has gained much attention due to their potential use as cancer therapeutics (20). Several compounds with different structures and binding modes have been discovered to date (31,34,37).…”

Section: Discussionmentioning

confidence: 99%

“…TNKS was originally discovered as a factor in telomere maintenance. It poly-ADP ribosylate (PARsylate)s telomeric repeat binding factor 1 (TRF1) and controls the binding of TRF1 to telomeric DNA (19,20). TNKS consists of three domains: a catalytic PARP domain, the ankyrin (ANK) domain, and the sterile alpha module (SAM) domain.…”

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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Tankyrase-targeted therapeutics: expanding opportunities in the PARP family

Cited by 248 publications

References 105 publications

Tankyrase Inhibition Blocks Wnt/β-Catenin Pathway and Reverts Resistance to PI3K and AKT Inhibitors in the Treatment of Colorectal Cancer

Tankyrase Inhibition Blocks Wnt/β-Catenin Pathway and Reverts Resistance to PI3K and AKT Inhibitors in the Treatment of Colorectal Cancer

USP25 regulates Wnt signaling by controlling the stability of tankyrases

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

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