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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Fatty acylation of Wnt proteins
Aaron H. Nile,Rami N. Hannoush +1 more
TL;DR: Progress in elucidating the biochemistry of Wnt fatty acylation is highlighted and a molecular view on the enzymology of substrate recognition and catalysis is provided, with a focus on the Wnt O-acyltransferase porcupine.
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Wnt/β-Catenin Signaling: The Culprit in Pancreatic Carcinogenesis and Therapeutic Resistance
Monish Ram Makena,Himavanth R. Gatla,Dattesh Verlekar,Sahithi Sukhavasi,Manoj K. Pandey,Kartick C. Pramanik +5 more
TL;DR: The role of Wnt signaling is summarized, future directions to enhance the survival of pancreatic cancer patients are suggested and limitations remain that must be overcome to increase the survival benefits associated with this emerging therapy.
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Modulating the wnt signaling pathway with small molecules
Freddi Huan Tran,Jie Zheng +1 more
TL;DR: Aiming to provide an overview of small molecules in a concise, easy‐to‐use manner, the current research on them is summarized and organized so that it may be helpful for utilization in different studies.
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Diversity of Precursor Lesions For Pancreatic Cancer: The Genetics and Biology of Intraductal Papillary Mucinous Neoplasm.
TL;DR: The clinical, biological, and genetic properties of IPMN are reviewed and various models for progression of these tumors to invasive PDA are discussed, providing a framework to better understand the diversity of the precursors for PDA.
Journal ArticleDOI
Cell Permeable Stapled Peptide Inhibitor of Wnt Signaling that Targets β-Catenin Protein-Protein Interactions.
Laura Dietrich,Bernd Rathmer,Kenneth Burnside Ramsay Ewan,Tanja Bange,Stefan Heinrichs,Trevor Clive Dale,Dennis Schade,Tom N. Grossmann,Tom N. Grossmann +8 more
TL;DR: A stapled peptide inhibitor is developed that targets the interaction between β-catenin and T cell factor/lymphoid enhancer-binding factor transcription factors, which are crucially involved in Wnt signaling and is generally useful for developing inhibitors of intracellular PPIs.
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