Reference Detail

Ref Type Journal Article
PMID (21393571)
Authors Gonsalves FC, Klein K, Carson BB, Katz S, Ekas LA, Evans S, Nagourney R, Cardozo T, Brown AM, DasGupta R
Title An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt/wingless signaling pathway.
Journal Proceedings of the National Academy of Sciences of the United States of America
Vol 108
Issue 15
Date 2011 Apr 12
URL
Abstract Text Misregulated β-catenin responsive transcription (CRT) has been implicated in the genesis of various malignancies, including colorectal carcinomas, and it is a key therapeutic target in combating various cancers. Despite significant effort, successful clinical implementation of CRT inhibitory therapeutics remains a challenging goal. This is, in part, because of the challenge of identifying inhibitory compounds that specifically modulate the nuclear transcriptional activity of β-catenin while not affecting its cytoskeletal function in stabilizing adherens junctions at the cell membrane. Here, we report an RNAi-based modifier screening strategy for the identification of CRT inhibitors. Our data provide support for the specificity of these inhibitory compounds in antagonizing the transcriptional function of nuclear β-catenin. We show that these inhibitors efficiently block Wnt/β-catenin-induced target genes and phenotypes in various mammalian and cancer cell lines. Importantly, these Wnt inhibitors are specifically cytotoxic to human colon tumor biopsy cultures as well as colon cancer cell lines that exhibit deregulated Wnt signaling.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
APC inact mut colon cancer sensitive iCRT-3 Preclinical Actionable In a preclinical study, iCRT-3 induced cell-cycle arrest and inhibited proliferation of colon cancer cells harboring APC inactivating mutations in culture (PMID: 21393571). 21393571
APC inact mut colon cancer sensitive iCRT-5 Preclinical Actionable In a preclinical study, iCRT-5 induced cell-cycle arrest and inhibited proliferation of colon cancer cells harboring APC inactivating mutations in culture (PMID: 21393571). 21393571
APC inact mut colon cancer sensitive iCRT-14 Preclinical - Cell line xenograft Actionable In a preclinical study, iCRT-14 induced cell-cycle arrest and inhibited proliferation of colon cancer cells harboring APC inactivating mutations in culture and decreased initial tumor growth in APC-mutant colon cancer cell line xenograft models (PMID: 21393571). 21393571