Identification of response signatures for tankyrase inhibitor treatment in tumor cell lines

Line Mygland,Kaja Lund,Ståle Nygård,Oleg Agafonov,Martin Frank Strand,Eva Lin,Max Lycke,Sandra Espada,Dorna Misaghian,Jenille Tan,Christian M Page,Tor Espen Thorvaldsen,Mike Costa,Jo Waaler,Yihong Yu,Aleksandra Aizenshtadt,Stefan Krauß ,Nai‐Wen Chi ,Nina Therese Solberg ,Petter Olsen

doi:10.1016/j.isci.2021.102807

Abstract

SummarySmall-molecule tankyrase 1 and tankyrase 2 (TNKS1/2) inhibitors are effective antitumor agents in selected tumor cell lines and mouse models. Here, we characterized the response signatures and the in-depth mechanisms for the antiproliferative effect of tankyrase inhibition (TNKSi). The TNKS1/2-specific inhibitor G007-LK was used to screen 537 human tumor cell lines and a panel of particularly TNKSi-sensitive tumor cell lines was identified. Transcriptome, proteome, and bioinformatic analyses revealed the overall TNKSi-induced response signatures in the selected panel. TNKSi-mediated inhibition of wingless-type mammary tumor virus integration site/β-catenin, yes-associated protein 1 (YAP), and phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT signaling was validated and correlated with lost expression of the key oncogene MYC and impaired cell growth. Moreover, we show that TNKSi induces accumulation of TNKS1/2-containing β-catenin degradasomes functioning as core complexes interacting with YAP and angiomotin proteins during attenuation of YAP signaling. These findings provide a contextual and mechanistic framework for using TNKSi in anticancer treatment that warrants further comprehensive preclinical and clinical evaluations.

Highlights

Anticancer treatment, using small-molecule tankyrase 1 and tankyrase 2 (TNKS1/2) inhibitors, shows in vivo efficacy against colorectal cancer (Lau et al, 2013; Waaler et al, 2012) and osteosarcoma (Martins-Neves et al, 2018) in mouse xenograft models
We show that tankyrase inhibition (TNKSi) induces accumulation of TNKS1/2-containing b-catenin degradasomes functioning as core complexes interacting with yes-associated protein 1 (YAP) and angiomotin proteins during attenuation of YAP signaling
These findings provide a contextual and mechanistic framework for using TNKSi in anticancer treatment that warrants further comprehensive preclinical and clinical evaluations

Summary

Introduction

Anticancer treatment, using small-molecule tankyrase 1 and tankyrase 2 (TNKS1/2) inhibitors, shows in vivo efficacy against colorectal cancer (Lau et al, 2013; Waaler et al, 2012) and osteosarcoma (Martins-Neves et al, 2018) in mouse xenograft models. The therapeutic effect can be enhanced and broadened by combining tankyrase inhibition (TNKSi) with inhibitors of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), epidermal growth factor receptor, or mitogen-activated protein kinase against colorectal cancer xenografts (Schoumacher et al, 2014; Solberg et al, 2018). Combining TNKSi with antibody-based inhibition of programmed cell death 1 has shown effect in syngeneic melanoma mouse models (Waaler et al, 2020b). Independent of the catalytic activity, TNKS1/2 provide structure-based scaffolding functions (Mariotti et al, 2016; Pollock et al, 2019; Seimiya and Smith, 2002)

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