Wnt addiction of genetically defined cancers reversed by PORCN inhibition
File(s)onc2015280a.pdf (4.42 MB)
Published version
Author(s)
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.
Date Issued
2015-08-10
Online Publication Date
2015-08-10
2016-07-12T12:19:09Z
Date Acceptance
2015-06-22
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/.
Source Database
pubmed
Identifier
onc2015280
Subjects
Oncology & Carcinogenesis
1112 Oncology And Carcinogenesis
1103 Clinical Sciences
Publication Status
Published