{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T20:14:21Z","timestamp":1760645661827},"reference-count":53,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2009,1,22]],"date-time":"2009-01-22T00:00:00Z","timestamp":1232582400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2009,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Tumor\u2010derived cell lines are indispensable tools for understanding the contribution of activated signaling pathways to the cancer phenotype and for the design and testing of targeted signal therapies. In our study, we characterize 10 colorectal carcinoma cell lines for the presence of mutations in the wnt, Ras\/MAPK, PI3K and p53 pathways. The mutational spectrum found in this panel of cell lines is similar to that detected in primary CRC, albeit with higher frequency of mutation in the \u03b2\u2010catenin and B\u2010Raf genes. We have monitored activation of the wnt and Ras\/MAPK pathways in these cells and analyzed their sensitivity to selective signaling inhibitors. Using \u03b2\u2010catenin subcellular distribution as a marker, we show that cells harboring APC mutations have low\u2010level activated wnt signaling, which can be blocked by the extracellular wnt inhibitor DKK\u20101, suggesting autocrine activation of this pathway; proliferation of these cells is also blocked by DKK\u20101. In contrast, cells with \u03b2\u2010catenin mutations are unresponsive to extracellular wnt inhibition. Constitutive phosphorylation of MAPK is present in the majority of the cell lines and correlates with B\u2010Raf but not K\u2010Ras mutations; correspondingly, the proliferation of cells harboring mutations in B\u2010Raf, but not K\u2010Ras, is exquisitely sensitive inhibition of the MAPK pathway. We find no correlation between PI3K mutation or loss of PTEN expression and increased sensitivity to PI3K inhibitors. Our study discloses clear\u2010cut differences in responsiveness to signaling inhibitors between individual mutations within an activated signaling pathway and suggests likely targets for signal\u2010directed therapy of colorectal carcinomas. \u00a9 2009 UICC<\/jats:p>","DOI":"10.1002\/ijc.24289","type":"journal-article","created":{"date-parts":[[2009,1,22]],"date-time":"2009-01-22T20:10:59Z","timestamp":1232655059000},"page":"297-307","source":"Crossref","is-referenced-by-count":35,"title":["Selective inhibition of proliferation in colorectal carcinoma cell lines expressing mutant APC or activated 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