Journal
CANCER RESEARCH
Volume 74, Issue 5, Pages 1495-1505Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-13-2682
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Funding
- Medical Research Council [U105192713]
- Cancer Research UK [C7379/A8709]
- Clinical Fellowship [C10112/A11388]
- NIHR Cambridge Biomedical Research Centre
- Cancer Research UK [15291, 11388] Funding Source: researchfish
- Medical Research Council [MC_U105192713, MC_U105184273] Funding Source: researchfish
- MRC [MC_U105184273, MC_U105192713] Funding Source: UKRI
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Hyperactive beta-catenin drives colorectal cancer, yet inhibiting its activity remains a formidable challenge. Interest is mounting in tankyrase inhibitors (TNKSi), which destabilize beta-catenin through stabilizing Axin. Here, we confirm that TNKSi inhibit Wnt-induced transcription, similarly to carnosate, which reduces the transcriptional activity of beta-catenin by blocking its binding to BCL9, and attenuates intestinal tumors in Apc(Min) mice. By contrast, beta-catenin's activity is unresponsive to TNKSi in colorectal cancer cells and in cells after prolonged Wnt stimulation. This TNKSi insensitivity is conferred by beta-catenin's association with LEF1 and BCL9-2/B9L, which accumulate during Wnt stimulation, thereby providing a feed-forward loop that converts transient into chronic beta-catenin signaling. This limits the therapeutic value of TNKSi in colorectal carcinomas, most of which express high LEF1 levels. Our study provides proof-of-concept that the successful inhibition of oncogenic beta-catenin in colorectal cancer requires the targeting of its interaction with LEF1 and/or BCL9/B9L, as exemplified by carnosate. (c) 2014 AACR.
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