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Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2013 Dec 10; Vol. 110 (50), pp. 20224-9. Date of Electronic Publication: 2013 Nov 25. - Publication Year :
- 2013
-
Abstract
- Wnt signaling is one of the key oncogenic pathways in multiple cancers, and targeting this pathway is an attractive therapeutic approach. However, therapeutic success has been limited because of the lack of therapeutic agents for targets in the Wnt pathway and the lack of a defined patient population that would be sensitive to a Wnt inhibitor. We developed a screen for small molecules that block Wnt secretion. This effort led to the discovery of LGK974, a potent and specific small-molecule Porcupine (PORCN) inhibitor. PORCN is a membrane-bound O-acyltransferase that is required for and dedicated to palmitoylation of Wnt ligands, a necessary step in the processing of Wnt ligand secretion. We show that LGK974 potently inhibits Wnt signaling in vitro and in vivo, including reduction of the Wnt-dependent LRP6 phosphorylation and the expression of Wnt target genes, such as AXIN2. LGK974 is potent and efficacious in multiple tumor models at well-tolerated doses in vivo, including murine and rat mechanistic breast cancer models driven by MMTV-Wnt1 and a human head and neck squamous cell carcinoma model (HN30). We also show that head and neck cancer cell lines with loss-of-function mutations in the Notch signaling pathway have a high response rate to LGK974. Together, these findings provide both a strategy and tools for targeting Wnt-driven cancers through the inhibition of PORCN.
- Subjects :
- Acyltransferases
Animals
Axin Protein antagonists & inhibitors
Blotting, Western
Cell Line, Tumor
Cloning, Molecular
High-Throughput Screening Assays
Humans
Mice
Mutagenesis
Phosphorylation drug effects
Pyrazines therapeutic use
Pyridines therapeutic use
Radioligand Assay
Rats
Receptors, Notch genetics
Reverse Transcriptase Polymerase Chain Reaction
Membrane Proteins antagonists & inhibitors
Neoplasms drug therapy
Pyrazines pharmacology
Pyridines pharmacology
Wnt Signaling Pathway drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 110
- Issue :
- 50
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 24277854
- Full Text :
- https://doi.org/10.1073/pnas.1314239110