Identification of response signatures for tankyrase inhibitor treatment in tumor cell lines
Small-molecule tankyrase 1 and tankyrase 2 (TNKS1/2) inhibitors work well antitumor agents in selected tumor cell lines and mouse models. Here, we characterised the response signatures and also the in-depth mechanisms for that antiproliferative aftereffect of tankyrase inhibition (TNKSi). The TNKS1/2-specific inhibitor G007-LK was utilized to screen 537 human tumor cell lines along with a panel of particularly TNKSi-sensitive tumor cell lines was identified. Transcriptome, proteome, and bioinformatic analyses revealed the general TNKSi-caused response signatures within the selected panel. TNKSi-mediated inhibition of wingless-type mammary tumor virus integration site/ß-catenin, yes-connected protein 1 (YAP), and phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT signaling was validated and correlated with lost expression from the key oncogene MYC and impaired cell growth. Furthermore, we reveal that TNKSi induces accumulation of TNKS1/2-that contains ß-catenin degradasomes functioning as core complexes getting together with YAP and angiomotin proteins during attenuation of YAP signaling. These bits of information give a contextual and mechanistic framework for implementing G007-LK TNKSi in anticancer treatment that warrants further comprehensive preclinical and clinical evaluations.