TNKS2 Inhibitor: Selective WNT Suppression via 8p Deletion

Nature Chemical Biology（Weill Cornell Medicine） USA

Overview

Researchers have developed a first-in-class TNKS2-selective inhibitor that targets a collateral vulnerability in cancers with chromosome 8p deletions. By exploiting a specific flexible loop in TNKS2, the inhibitor suppresses WNT signaling in TNKS1-deficient cells while avoiding the on-target toxicities associated with broad TNKS1/2 inhibition.

In Depth

Key Findings

The study identifies a tumor-restricted dependency on tankyrase 2 (TNKS2) in cancers characterized by the genomic loss of chromosome 8p. In these tumors, the reduction or absence of tankyrase 1 (TNKS1) creates a collateral vulnerability where WNT pathway activity is regulated primarily by TNKS2. Using structure-guided design, the researchers developed a first-in-class TNKS2-selective small-molecule inhibitor that suppresses growth in TNKS1-deleted cell and organoid models without affecting TNKS1-diploid cells.

Technical Details

TNKS1 and TNKS2 are PARP-family enzymes that promote WNT signaling by driving the PARylation and degradation of AXIN1, a negative regulator. While broad inhibition of both enzymes stabilizes AXIN1 and downregulates WNT, it typically causes dose-limiting tissue toxicity. The researchers discovered a flexible loop in TNKS2 that allows for selective drug targeting. Data from the TCGA PanCancer Atlas and ICGC show that approximately half of lung, breast, liver, prostate, and colon cancers carry heterozygous or homozygous 8p deletions. In TNKS1 knockout (KO) and heterozygous (Het) DLD1 clones, TNKS2 silencing alone was sufficient to stabilize AXIN1, whereas 8p diploid cells required the suppression of both TNKS1 and TNKS2 to achieve the same effect.

Background & Context

Hyperactive WNT signaling is a driver in numerous cancers, including colorectal cancer (CRC), where it is a near-ubiquitous feature. While targeting WNT has high clinical potential, previous inhibitors have been hampered by toxicity in healthy tissues. The 8p chromosome arm contains several potential tumor suppressor genes, including DLC1, FGL1, and TRIM35, but the specific loss of the TNKS1 locus creates the unique dependency on TNKS2 observed in this research.

Significance & Outlook

This approach provides a method to achieve tumor-restricted WNT suppression, potentially overcoming the safety barriers that have limited previous WNT-targeted therapies. By targeting a cancer-specific genomic vulnerability, this modality offers a new therapeutic strategy for multiple epithelial cancer types exhibiting 8p deletions.

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