The tankyrase inhibitor G007-LK inhibits small intestine LGR5+ stem cell proliferation without altering tissue morphology

Background: The Wnt pathway regulates intestinal stem cells and is frequently disrupted in intestinal adenomas. The pathway contains several potential biotargets for interference, including the poly-ADP ribosyltransferase enzymes tankyrase1 and 2. LGR5 is a known Wnt pathway target gene and marker of intestinal stem cells. The LGR5⁺ stem cells are located in the crypt base and capable of regenerating all intestinal epithelial cell lineages.

Results: We treated Lgr5-EGFP-Ires-CreERT2;R26R-Confetti mice with the tankyrase inhibitor G007-LK for up to 3 weeks to assess the effect on duodenal stem cell homeostasis and on the integrity of intestinal epithelium. At the administered doses, G007-LK treatment inhibited Wnt signalling in LGR5⁺ stem cells and reduced the number and distribution of cells traced from duodenal LGR5⁺ stem cells. However, the gross morphology of the duodenum remained unaltered and G007-LK-treated mice showed no signs of weight loss or any other visible morphological changes. The inhibitory effect on LGR5⁺ stem cell proliferation was reversible.

Conclusion: We show that the tankyrase inhibitor G007-LK is well tolerated by the mice, although proliferation of the LGR5⁺ intestinal stem cells was inhibited. Our observations suggest the presence of a tankyrase inhibitor-resistant cell population in the duodenum, able to rescue tissue integrity in the presence of G007-LK-mediated inhibition of the Wnt signalling dependent LGR5⁺ intestinal epithelial stem cells.