A potent and selective TNKS2 inhibitor for tumor-selective WNT suppression

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Hyperactive WNT signaling drives cancer, but WNT inhibitors face toxicity issues.
• Tankyrase (TNKS) inhibitors can constrain WNT signaling but lack tumor selectivity.
• Existing TNKS inhibitors affect both tumor and healthy tissues, limiting clinical use.

Purpose of the Study:

• To identify a tumor-selective approach for inhibiting WNT signaling.
• To investigate the role of chromosome 8p loss in creating a vulnerability for Tankyrase inhibition.
• To develop a TNKS2-selective inhibitor for targeted WNT pathway suppression in cancer.

Main Methods:

• Analysis of chromosome 8p loss in advanced epithelial malignancies.
• Assessment of Tankyrase 1 (TNKS1) and Tankyrase 2 (TNKS2) expression in relation to 8p loss.
• Structure-guided drug design to identify a TNKS2-selective inhibitor.
• Testing the inhibitor in TNKS1-deficient cancer cell and organoid models.

Main Results:

• Chromosome 8p loss, common in epithelial cancers, leads to TNKS1 depletion.
• This 8p loss creates a tumor-specific dependency on the TNKS2 protein.
• A novel, first-in-class TNKS2-selective inhibitor was identified.
• The inhibitor selectively suppressed WNT signaling in TNKS1-deficient cancer models.

Conclusions:

• Chromosome 8p loss represents a targetable vulnerability in multiple cancer types.
• TNKS2-selective inhibition offers a strategy for potent and selective WNT-targeted cancer therapy.
• This approach may overcome the on-target toxicity issues associated with broader WNT inhibitors.