Wnt addiction of genetically defined cancers reversed by PORCN inhibition
Babita Madan,Zhiyuan Ke,Nathan Harmston,Soo Yei Ho,A O Frois,Jenefer Alam,Duraiswamy Athisayamani Jeyaraj,Vishal Pendharkar,Kakaly Ghosh,I H Virshup,Vithya Manoharan,Esther Hq Ong,Kanda Sangthongpitag,Jeffrey Hill,Enrico Petretto,Thomas H. Keller,May Ann Lee,Alex Matter,David M. Virshup,David M. Virshup +19 more
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TLDR
A novel potent, orally available PORCN inhibitor, ETC-1922159, that blocks the secretion and activity of all Wnts is developed that is remarkably effective in treating RSPO-translocation bearing colorectal cancer patient-derived xenografts.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.read more
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Multi‑layered prevention and treatment of chronic inflammation, organ fibrosis and cancer associated with canonical WNT/β‑catenin signaling activation (Review).
TL;DR: β-catenin and NF-κB signaling activation are involved in field cancerization in the stomach associated with Helicobacter pylori infection and in the liver associated with hepatitis C virus (HCV) infection and other etiologies.
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Protein Lipidation in Cell Signaling and Diseases: Function, Regulation, and Therapeutic Opportunities.
TL;DR: Recent progress is highlighted in the understanding of protein lipidation, in particular, S-palmitoylation and lysine fatty acylation, and the importance of these modifications for protein regulation, cell signaling, and diseases is described.
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Wnt Signaling and Drug Resistance in Cancer
Zheng Zhong,David M. Virshup +1 more
TL;DR: Recent studies extend understanding of this ancient signaling pathway and describe the development and improvement of anti-Wnt therapeutic modalities for cancer.
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Control of Wnt Receptor Turnover by R-spondin-ZNRF3/RNF43 Signaling Module and Its Dysregulation in Cancer.
TL;DR: The biology of the R-spondin-ZNRF3/RNF43 signaling module, cancer-associated alterations of this signaling module and their value as biomarkers to identify Wnt-addicted tumors are discussed.
Journal ArticleDOI
Cellular and molecular architecture of the intestinal stem cell niche
TL;DR: How recent mRNA profiles of mouse and human intestinal submucosa, coupled with fine-resolution microscopy and gene and cell disruptions, reveal a coherent picture of an organised tissue carrying cells with distinct molecular properties and functions is discussed.
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