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 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/b-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 b-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.

Small-Molecule Inhibitors of Tankyrases as Prospective Therapeutics for Cancer

“…As a standalone agent, this molecule was screened against a panel of 537 human cancer cell lines originating from 29 different tissues with diverse primary diagnoses, and it was found to inhibit signal transduction pathways including WNT/β-catenin, Hippo, and PTEN/AKT in sensitive cancer cell lines in a context-dependent manner. 191 Such inhibition led to reduced expression of the MYC protooncogene, induced a cytostatic or cytotoxic effect, and ultimately impaired the growth of cancer cells. As part of combination regimens, G007-LK was used with inhibitors of kinases (including AKT, 122 MEK, 122,192 PI3K and EGFR, 193 and CDK4 121 ), chemotherapeutic drugs (like irinotecan 163 and temozolomide 194 ), and anti-PD-1 immune checkpoint therapy; 195 enhanced antiproliferative effects were detected on colorectal cancer and HCC cell lines as well as on glioma stem cells.…”

“…As one of the early-generation tankyrase inhibitors, G007-LK has inevitably been employed to interrogate a multitude of cancer cell lines. As a standalone agent, this molecule was screened against a panel of 537 human cancer cell lines originating from 29 different tissues with diverse primary diagnoses, and it was found to inhibit signal transduction pathways including WNT/β-catenin, Hippo, and PTEN/AKT in sensitive cancer cell lines in a context-dependent manner . Such inhibition led to reduced expression of the MYC proto-oncogene, induced a cytostatic or cytotoxic effect, and ultimately impaired the growth of cancer cells.…”

Exploring the Wnt Pathway as a Therapeutic Target for Prostate Cancer

“…Tankyrases are a family of polymerases that can regulate a number of cellular processes, including proliferation, differentiation, DNA damage repair, and metabolism [ 251 ]. Tankyrase1/2 form a distinct subgroup with functional and structural similarities that regulate protein substrates through poly(ADP-ribosyl)ation (PARylation) post-translational modifications and can coordinate a number of cell signaling pathways, including Wnt/β-catenin, YAP, AKT, and NOTCH signaling [ 251 , 252 ]. Tankyrase1/2 can stabilize the Wnt inhibitor AXIN1, resulting in destabilization of the β-catenin destruction complex [ 253 ].…”

ADP-Ribosylation as Post-Translational Modification of Proteins: Use of Inhibitors in Cancer Control

“…In this optic, tankyrase promotes Wnt signaling, while TNKS inhibitors are useful in the treatment of Wnt-driven cancers [ 31 , 104 ]. G007-LK is a selective tankyrase inhibitor [ 105 ]: the treatment with this inhibitor induced the loss of expression of MYC and impaired cell growth, with the accumulation of β-catenin degradasomes. IWR1 and AZ-6102 are also selective for tankyrase [ 106 ].…”