Tankyrase Inhibition Causes Reversible Intestinal Toxicity in Mice with a Therapeutic Index < 1

Area of Science:

• Oncology
• Gastroenterology
• Pharmacology

Background:

• Activated Wnt/β-catenin signaling is a hallmark of colorectal cancer.
• Wnt pathway inhibitors, including tankyrase inhibitors, are investigated as anticancer therapies.
• Wnt signaling is crucial for intestinal homeostasis, and inhibitors can cause toxicity.

Purpose of the Study:

• To characterize the intestinal toxicity of tankyrase inhibitors.
• To assess the reversibility and therapeutic index of novel tankyrase inhibitor G-631.
• To evaluate the potential clinical utility of tankyrase inhibitors in colorectal cancer treatment.

Main Methods:

• Administration of novel tankyrase inhibitor G-631 to mice at various doses.
• Assessment of intestinal toxicity, including histopathological changes (enteritis, villus blunting, degeneration, inflammation).
• Evaluation of antitumor activity in a colorectal cancer xenograft model and toxicity reversibility post-treatment.

Main Results:

• G-631 induced dose-dependent intestinal toxicity with a therapeutic index < 1 in mice.
• Subtherapeutic doses caused reversible enteritis; higher doses led to severe necrotizing enteritis, morbidity, and only partial recovery.
• Weak antitumor activity was observed, but severe intestinal toxicity limited therapeutic potential.

Conclusions:

• Tankyrase inhibitors exhibit significant on-target intestinal toxicity.
• The therapeutic index of G-631 is < 1 in mice, limiting its clinical utility for colorectal cancer.
• Intestinal toxicity and limited therapeutic window pose challenges for developing tankyrase inhibitors as anticancer agents.