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	Vol	Issue	Date	Pages	Journal Short Title
Proceedings of the National Academy of Sciences of the United States of America	108	15	2011 Apr 12	5954-63	Proc Natl Acad Sci U S A

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

Gene	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-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
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