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Adenomatous polyposis coli (APC) truncations occur in many colorectal cancers and are often associated with immune infiltration. The aim of this study was to determine whether a combination of Wnt inhibition with anti-inflammatory (sulindac) and/or proapototic (ABT263) drugs can reduce colon adenomas. Apc min/+ and doublecortin-like kinase 1 ( Dclk1 ) Cre/+ ;Apc fl/fl mice were exposed to dextran sulphate sodium (DSS) in their drinking water to promote the formation of colon adenomas. Mice were then treated with either a Wnt-signaling antagonist pyrvinium pamoate (PP), an anti-inflammatory agent sulindac or proapoptotic compound ABT263 or a combination of PP+ABT263, or PP+sulindac. Colon adenoma frequency, size, and T-cell abundance were measured. DSS treatment resulted in significant increases in colon adenoma number ( P < 0.001, n > 5) and burden in Apc min/+ ( P < 0.01, n > 5) and Dclk1 Cre/+ ;Apc fl/fl ( P < 0.02, n > 5) mice. There was no effect on adenomas following treatment with PP in combination with ABT263. Adenoma number and burden were reduced with PP+sulindac treatment in Dclk1 Cre/+ ; Apc fl/fl mice ( P < 0.01, n > 17) and in Apc min/+ mice ( P < 0.001, n > 7) treated with sulindac or PP+sulindac with no detectable toxicity. PP treatment of Apc min/+ mice increased the frequency of CD3 + cells in the adenomas. The combination of Wnt pathway inhibition with sulindac was more effective in Dclk1 Cre/+ ; Apc fl/fl mice and provides an opportunity for killing Apc -mutant colon adenoma cells, indicating a strategy for both colorectal cancer prevention and potential new treatments for patients with advanced colorectal cancer. Outcomes from the results of this study may be translatable to the clinic for management of FAP and other patients with a high risk of developing colorectal cancer., Significance: Colorectal cancer is one of the most common cancers worldwide with limited therapeutic options. APC and other Wnt signaling mutations occur in the majority of colorectal cancers but there are currently no Wnt inhibitors in the clinic. The combination of Wnt pathway inhibition with sulindac provides an opportunity for killing Apc -mutant colon adenoma cells and suggests a strategy for colorectal cancer prevention and new treatments for patients with advanced colorectal cancer., Competing Interests: M.C. Faux reports grants from National Health and Medical Research Council of Australia during the conduct of the study. No other disclosures were reported., (© 2022 The Authors; Published by the American Association for Cancer Research.)