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

Small-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-speci...

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Bibliographic Details
Published in:iScience 2021-07, Vol.24 (7), p.102807-102807, Article 102807
Main Authors: Mygland, Line, Brinch, Shoshy Alam, Strand, Martin Frank, Olsen, Petter Angell, Aizenshtadt, Aleksandra, Lund, Kaja, Solberg, Nina Therese, Lycke, Max, Thorvaldsen, Tor Espen, Espada, Sandra, Misaghian, Dorna, Page, Christian M., Agafonov, Oleg, Nygård, Ståle, Chi, Nai-Wen, Lin, Eva, Tan, Jenille, Yu, Yihong, Costa, Mike, Krauss, Stefan, Waaler, Jo
Format: Article
Language:English
Subjects:
Cancer
Proteomics
Transcriptomics
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Summary:Small-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. [Display omitted] •TNKSi-responding tumor cell lines were identified•TNKSi targets WNT/β-catenin, YAP, and PI3K/AKT signaling•Reduced MYC expression leads to impaired tumor cell growth Proteomics; Cancer; Transcriptomics
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2021.102807