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

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 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.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Lung Cancer,Colon Cancer,Kidney Cancer,Malignant Neoplasm Of Ovary

SUBMITTER: Martin Strand  

LAB HEAD: Jo Waaler

PROVIDER: PXD022908 | Pride | 2021-09-09

REPOSITORIES: Pride