文章基本信息

标题：Identification of response signatures for tankyrase inhibitor treatment in tumor cell lines
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作者：Line Mygland ; Shoshy Alam Brinch ; Martin Frank Strand 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：7
页码：1-27
DOI：10.1016/j.isci.2021.102807
语种：English
出版社：Elsevier
摘要：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.Graphical abstractDisplay OmittedHighlights•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 growthProteomics; Cancer; Transcriptomics