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
Citations
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A p300/GATA6 axis determines differentiation and Wnt dependency in pancreatic cancer models
TL;DR: It is found that EP300 is silenced due to genetic alterations in all the existing RNF43-mutant pancreatic cancer cell lines that are resistant to PORCN inhibitors, rendering these cancer cells resistant to Wnt inhibition.
Journal ArticleDOI
Cross-Talk between Wnt Signaling and Src Tyrosine Kinase
TL;DR: It is noted that aberrant regulation of these components give rise to various diseases including typically cancer, and as such, merit a closer look.
Journal ArticleDOI
Broad regulation of gene isoform expression by Wnt signaling in cancer.
Muhammad Idris,Nathan Harmston,Nathan Harmston,Enrico Petretto,Babita Madan,David M. Virshup,David M. Virshup +6 more
TL;DR: Deep time-resolved RNA-seq in two independent in vivo Wnt-addicted tumor models during treatment with the potent Wnt inhibitor ETC-159 found 1,025 genes that underwent Wnt regulated variable exon usage leading to isoform expression changes, suggesting that the Wntregulated splicing events are components of fundamental oncogenic processes.
Journal ArticleDOI
Determination of the membrane topology of PORCN, an O-acyl transferase that modifies Wnt signalling proteins
Lisa M. Galli,Marc O. Anderson,J. Gabriel Fraley,Luis Sanchez,Raymund Bueno,David N. Hernandez,Eva U. Maddox,Vishwanath R. Lingappa,Laura W. Burrus +8 more
TL;DR: In this paper, the authors used experimental data along with homology modelling to determine the membrane topology of PORCN, a membrane-bound O-acyl transferase (MBOAT) that catalyses the addition of monounsaturated palmitate to Wnt proteins and is required for Wnt gradient formation and signalling.
Journal ArticleDOI
A p300/GATA6 axis determines differentiation and Wnt dependency in pancreatic cancer models
TL;DR: Wang et al. as discussed by the authors performed in vivo CRISPR screens in PORCN inhibitor-sensitive RNF43-mutant pancreatic cancer xenografts and identified genes in the Wnt pathway whose loss conferred drug resistance, including APC, AXIN1, and CTNNBIP1.
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