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.

Wnt/beta-catenin pathway: modulating anticancer immune response

“…Waaler et al demonstrated the antitumoral effect of inhibiting tankyrase in a model of colorectal adenoma and adenocarcinoma [70]. Potential adverse events of this therapy include diarrhea and intestinal toxicity [71]. Tankyrase inhibition has been shown to revert resistance to PI3K and AKT inhibitors in colorectal cancer patient-derived sphere cultures and mouse tumor xenografts [72].…”

Differential abundance of CK1α provides selectivity for pharmacological CK1α activators to target WNT-dependent tumors

“…A significant hurdle to the clinical development of WNT inhibitors is overcoming the on-target toxicity that results from effects on the WNT-dependent intestinal stem cells that drive normal gastrointestinal (GI) homeostasis (24, 25). Such dose-limiting on-target toxicities have been observed using both Tankyrase and Porcupine inhibitors (23, 26, 27), with continuous dosing of both classes of small molecules disrupting normal GI structure and function. Thus, there appears to be only a limited therapeutic window for Porcupine and TANKi, which might ultimately limit their clinical utility.…”

Delivery of the Porcupine Inhibitor WNT974 in Mice

“…Although suppression of Wnt pathway activity with inhibitors targeting the Tankyrase enzymes which indirectly control β-catenin abundance by regulating the stability of its destruction complex is anticipated to have a poor therapeutic index, porcupine inhibitors appear to be relatively well tolerated [8, 9]. Thus, Porcn inhibitors such as WNT974 enable a variety of preclinical studies focused on Wnt signaling while limiting the potential influence of unwanted side effects on test outcomes.…”