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

ABSTRACT: Anti-cancer treatment, using small-molecule tankyrase 1 and tankyrase 2 (TNKS1/2) inhibition (TNKSi) shows effect against selected tumor cell lines and in mouse models. Here, we characterize the responsiveness signatures and in depth mechanisms for the anti-proliferative effect of TNKSi. The TNKS1/2-specific inhibitor G007-LK was screened against 537 human tumor cell lines, and a panel of in particular TNKSi-sensitive tumor cell lines was identified. Transcriptome, proteome and bioinformatic analyses classified the overall TNKSi-induced response signatures in the selected panel. Prediction of 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, when attenuating YAP signaling, induces accumulation of TNKS1/2-containing β-catenin degradosomes functioning as central complexes interacting with YAP and AMOT proteins. The findings provide a contextual and mechanistic framework for TNKSi in cancer cell lines rationalizing further comprehensive preclinical and clinical evaluations.

ORGANISM(S): Homo sapiens

PROVIDER: GSE162648 | GEO | 2021/06/18

REPOSITORIES: GEO

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

Project description: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 in particular 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 central complexes interacting with YAP and AMOT proteins during attenuation of YAP signaling. These findings provide a contextual and mechanistic framework for using TNKSi in anti-cancer treatment that warrants further comprehensive preclinical and clinical evaluations.

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