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Department of Oncology, Lombardi Cancer Center, Georgetown University School of Medicine, Washington, DC 20057

Activation of ß-catenin is a critical step in the pathogenesis of many common human cancers and is the initiating event in adenocarcinoma of the colon. Because activation of ß-catenin provides a gain-of-function, it is tempting to speculate that specific pharmacological inhibition of activated ß-catenin might reverse the tumorigenic properties of human cancer cells and therefore form the basis of an effective anticancer strategy. In an effort to provide proof-of-principle for such a strategy, we used a novel clonal growth assay based on human somatic cell gene targeting to determine whether activated ß-catenin remains a necessary oncogenic stimulus in advanced human cancer cells. Using this approach, we demonstrate that ß-catenin is a necessary oncogene in human SW48 and DLD1 colon cancer cells but not in HCT116 cells. These data indicate that activated ß-catenin can remain a critical oncogenic stimulus throughout the progression of human colon cancer and suggest that the small molecule inhibitors of activated ß-catenin currently under development will be effective anticancer therapeutics in a subset of malignant colon cancers.

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