Tankyrases as drug targets

Lehtiö, L.; Chi, Nai‐Wen; Krauß, Stefan

doi:10.1111/febs.12320

Cited by 162 publications

(176 citation statements)

References 113 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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“…TNKS1/2 are involved in a wide range of cellular functions (10) and were recently shown to positively regulate the WNT/b-catenin pathway through poly-ADP-ribosylation of AXIN (11), the rate-limiting factor for destruction complex stability and function (12). Implication of TNKS1/2 as druggable targets in the WNT/b-catenin signaling pathway has generated profound research on developing novel small-molecule inhibitors (9,13,14). Inhibition of the catalytic activity of TNKS1/2 reduces WNT/b-catenin signaling in both APC wild-type cells (e.g., in HEK293) and colorectal cancer cells harboring APC truncations (e.g., in SW480; refs.…”

Section: Introductionmentioning

confidence: 99%

Structure, Dynamics, and Functionality of Tankyrase Inhibitor-Induced Degradasomes

Thorvaldsen

Pedersen

Wenzel

et al. 2015

Molecular Cancer Research

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Tankyrase (TNKS) enzymes, due to their poly(ADP-ribose) polymerase activity, have emerged as potential targets in experimental cancer therapy. However, the functional consequences of TNKS inhibition remain incompletely resolved because of the binding promiscuity of TNKS. One of the hallmarks of small-molecule TNKS inhibitors (TNKSi) is the stabilization of AXIN, which plays a pivotal role in the WNT/b-catenin signaling pathway. The present study focused on the known ability of TNKSi to induce cytoplasmic puncta (degradasomes) consisting of components of the signallimiting WNT/b-catenin destruction complex. Using the colorectal cancer cell line SW480 stably transfected with GFP-TNKS1, it was demonstrated that a TNKS-specific inhibitor (G007-LK) induces highly dynamic and mobile degradasomes that contain phosphorylated b-catenin, ubiquitin, and b-TrCP. Likewise, G007-LK was found to induce similar degradasomes in other colorectal cancer cell lines expressing wild-type or truncated versions of the degradasome component APC. Super-resolution and electron microscopy revealed that the induced degradasomes in SW480 cells are membrane-free structures that consist of a filamentous assembly of high electron densities and discrete subdomains of various destruction complex components. Fluorescence recovery after photobleaching experiments further demonstrated that b-catenin-mCherry was rapidly turned over in the G007-LK-induced degradasomes, whereas GFP-TNKS1 remained stable. In conclusion, TNKS inhibition attenuates WNT/b-catenin signaling by promoting dynamic assemblies of functional active destruction complexes into a TNKS-containing scaffold even in the presence of an APC truncation.Implications: This study demonstrates that b-catenin is rapidly turned over in highly dynamic assemblies of WNT destruction complexes (degradasomes) upon tankyrase inhibition and provides a direct mechanistic link between degradasome formation and reduced WNT signaling in colorectal cancer cells.

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“…3 Tankyrases (TNKS-1 and -2) are also emerging as drug targets in oncology, but for most of the other PARPs, the precise biological functions remain largely unclear. 3,4 As the clinical trials with PARP inhibitors are in progress, the interest in understanding the extent of their cross-reactivity with other members of the ARTD family increases, especially in view of long-term therapies. 5,6 PARP inhibitors are generally designed to compete with NAD + at the enzyme active site; therefore, they have the potential to inhibit different members of the ARTD family or other enzymes that use NAD + as substrate.…”

Section: Introductionmentioning

confidence: 99%

Insights into PARP Inhibitors’ Selectivity Using Fluorescence Polarization and Surface Plasmon Resonance Binding Assays

et al. 2014

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PARP inhibitors are an exciting new class of antineoplastic drugs that have been proven to be efficacious as single agents in cancer settings with inherent DNA repair defects, as well as in combination with DNA-damaging chemotherapeutics. Currently, they are designed to target the catalytic domain of PARP-1, the most studied member of the family, with a key role in the DNA-damage repair process. Because PARP inhibitors are substrate (NAD + ) competitors, there is a need for a deeper understanding of their cross-reactivity. This is particularly relevant for PARP-2, the PARP-1 closest homologue, for which an embryonic lethal phenotype has been observed in double knockout mice. In this study, we describe the development and validation of binding assays based on fluorescence polarization (FP) and surface plasmon resonance (SPR) techniques. PARP-1, PARP-2, PARP-3, and TNKS-1 FP displacement assays are set up by employing ad hoc synthesized probes. These assays are suitable for high-throughput screening (HTS) and selectivity profiling, thus allowing the identification of NAD + binding site selective inhibitors. The PARP-1 and PARP-2 complementary SPR binding assays confirm displacement data and the in-depth inhibitor characterization. Moreover, these formats have the potential to be broadly applicable to other members of the PARP family.

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Tankyrases as drug targets

Cited by 162 publications

References 113 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

Structure, Dynamics, and Functionality of Tankyrase Inhibitor-Induced Degradasomes

Insights into PARP Inhibitors’ Selectivity Using Fluorescence Polarization and Surface Plasmon Resonance Binding Assays

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