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Wnt addiction of genetically defined cancers reversed by PORCN inhibition

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Title: Wnt addiction of genetically defined cancers reversed by PORCN inhibition
Authors: Madan, B
Ke, Z
Harmston, N
Ho, SY
Frois, AO
Alam, J
Jeyaraj, DA
Pendharkar, V
Ghosh, K
Virshup, IH
Manoharan, V
Ong, EH
Sangthongpitag, K
Hill, J
Petretto, E
Keller, TH
Lee, MA
Matter, A
Virshup, DM
Item Type: Journal Article
Abstract: Enhanced sensitivity to Wnts is an emerging hallmark of a subset of cancers, defined in part by mutations regulating the abundance of their receptors. Whether these mutations identify a clinical opportunity is an important question. Inhibition of Wnt secretion by blocking an essential post-translational modification, palmitoleation, provides a useful therapeutic intervention. We developed a novel potent, orally available PORCN inhibitor, ETC-1922159 (henceforth called ETC-159) that blocks the secretion and activity of all Wnts. ETC-159 is remarkably effective in treating RSPO-translocation bearing colorectal cancer (CRC) patient-derived xenografts. This is the first example of effective targeted therapy for this subset of CRC. Consistent with a central role of Wnt signaling in regulation of gene expression, inhibition of PORCN in RSPO3-translocated cancers causes a marked remodeling of the transcriptome, with loss of cell cycle, stem cell and proliferation genes, and an increase in differentiation markers. Inhibition of Wnt signaling by PORCN inhibition holds promise as differentiation therapy in genetically defined human cancers.
Issue Date: 10-Aug-2015
Date of Acceptance: 22-Jun-2015
URI: http://hdl.handle.net/10044/1/34642
DOI: http://dx.doi.org/10.1038/onc.2015.280
ISSN: 1476-5594
Publisher: Nature Publishing Group
Start Page: 2197
End Page: 2207
Journal / Book Title: Oncogene
Volume: 35
Issue: 17
Copyright Statement: This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Keywords: Oncology & Carcinogenesis
1112 Oncology And Carcinogenesis
1103 Clinical Sciences
Publication Status: Published
Appears in Collections:Clinical Sciences
Molecular Sciences
Faculty of Medicine



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