Abstract
Small-molecule tankyrase 1 and tankyrase 2 (TNKS1/2) inhibitors are effective anti-tumor agents in selected tumor cell lines and mouse models . Here, we characterized the response signatures and the in-depth mechanisms for the anti-proliferative 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 WNT/β-catenin, YAP and PI3K/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 AMOT proteins during attenuation of YAP signaling. These findings p rovide a contextual and mechanistic framework for using TNKSi in anti-cancer 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
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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