GSE162648
Identification of response signatures for tankyrase inhibitor treatment in tumor cell lines
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/ß-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 ß-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. Overall design: Two biological replicates of 5 different cancer cell lines were treated with DMSO (0.01%) control or G007-LK (1 µM),  24 hours before RNA extraction