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Ref Type Journal Article
PMID (26692561)
Authors Zhong Y, Katavolos P, Nguyen T, Lau T, Boggs J, Sambrone A, Kan D, Merchant M, Harstad E, Diaz D, Costa M, Schutten M
Title Tankyrase Inhibition Causes Reversible Intestinal Toxicity in Mice with a Therapeutic Index < 1.
Abstract Text Activated Wnt/β-catenin signaling is frequently associated with colorectal cancer. Wnt inhibitors, including tankyrase inhibitors, are being explored as potential anticancer agents. Wnt signaling is also critical for intestinal tissue homeostasis, and Wnt inhibitors have been shown to cause intestinal toxicity in mice by affecting intestinal stem cells. This study sought to characterize the intestinal toxicity of tankyrase inhibitors, including reversibility, and to assess their therapeutic index. Novel tankyrase inhibitor G-631 caused dose-dependent intestinal toxicity with a therapeutic index < 1 after 14 days of dosing in mice. At a tolerated subtherapeutic dose level, the intestinal toxicity was composed of enteritis characterized by villus blunting, epithelial degeneration, and inflammation, which fully reversed after 14 days of recovery. Doubled exposure showed weak antitumor activity in a xenograft colorectal cancer model but also caused more severe intestinal toxicity characterized by multifocal-regionally extensive necrotizing and ulcerative enteritis leading to morbidity or moribundity in some animals. This toxicity was only partially reversed after 14 days of recovery, with evidence of crypt and villus regeneration, mildly blunted villi, and/or scarring in association with chronic inflammation of the submucosa. Therefore, the clinical utility of tankyrase inhibitors is likely limited by the on-target intestinal toxicity and a therapeutic index < 1 in mice.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
G-631 G-631 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
G-631 Tankyrase Inhibitor 11 G-631 inhibits Tankyrase 1 and 2 (TNK1, TNK2), resulting in decreased Wnt/Beta-catenin pathway signaling, but has little anti-tumor activity and leads to intestinal toxicity (PMID: 26692561).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
APC mutant colorectal cancer no benefit G-631 Preclinical - Cell line xenograft Actionable In a preclinical study, G-631 inhibited Wnt pathway signaling in colorectal cancer cell line xenograft models harboring an APC mutation, but demonstrated little anti-tumor activity and led to intestinal toxicity (PMID: 26692561). 26692561