title: Tankyrase Inhibition Causes Reversible Intestinal Toxicity in Mice with a Therapeutic Index < 1.
abstract: 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.
authors.affiliation: Departments of Safety Assessment, Genentech Inc., South San Francisco, California, USA zhong.yu@gene.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Departments of Safety Assessment, Genentech Inc., South San Francisco, California, USA.
authors.forename: Paula
authors.initials: P
authors.lastname: Katavolos
authors.affiliation: Departments of Safety Assessment, Genentech Inc., South San Francisco, California, USA.
authors.forename: Trung
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Discovery Oncology, Genentech Inc., South San Francisco, California, USA.
authors.forename: Ted
authors.initials: T
authors.lastname: Lau
authors.affiliation: Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, California, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Boggs
authors.affiliation: Pharmaceutical Sciences, Genentech Inc., South San Francisco, California, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Sambrone
authors.affiliation: Translational Oncology, Genentech Inc., South San Francisco, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Kan
authors.affiliation: Translational Oncology, Genentech Inc., South San Francisco, California, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Merchant
authors.affiliation: Departments of Safety Assessment, Genentech Inc., South San Francisco, California, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Harstad
authors.affiliation: Departments of Safety Assessment, Genentech Inc., South San Francisco, California, USA.
authors.forename: Dolores
authors.initials: D
authors.lastname: Diaz
authors.affiliation: Discovery Oncology, Genentech Inc., South San Francisco, California, USA.
authors.forename: Mike
authors.initials: M
authors.lastname: Costa
authors.affiliation: Departments of Safety Assessment, Genentech Inc., South San Francisco, California, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Schutten
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D038501:Tankyrases / Q000037:antagonists & inhibitors*; D018675:Toxicity Tests; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D038501:Tankyrases
keywords: Wnt; colorectal cancer; intestinal stem cell; reversibility; tankyrase; therapeutic index; toxicity