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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Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities.
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From tumour heterogeneity to advances in precision treatment of colorectal cancer
TL;DR: Advances in molecular biology over the past decade have enabled a better understanding of the development of CRC, as well as the more-precise use of innovative targeted therapies for this disease, and include three fundamental achievements.
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Recurrent R-spondin fusions in colon cancer
Somasekar Seshagiri,Eric Stawiski,Steffen Durinck,Zora Modrusan,Elaine E. Storm,Caitlin B. Conboy,Subhra Chaudhuri,Yinghui Guan,Vasantharajan Janakiraman,Bijay S. Jaiswal,Joseph Guillory,Connie Ha,Gerrit J. P. Dijkgraaf,Jeremy Stinson,Florian Gnad,Melanie A. Huntley,Jeremiah D. Degenhardt,Peter M. Haverty,Richard Bourgon,Weiru Wang,Hartmut Koeppen,Robert Gentleman,Timothy K. Starr,Zemin Zhang,David A. Largaespada,Thomas D. Wu,Frederic J. de Sauvage +26 more
TL;DR: The R-spondin gene fusions, several new recurrent mutations in the Wnt pathway gene TCF7L2, chromatin-remodelling genes such as TET2 and TET3 and receptor tyrosine kinases including ERBB3 are identified and shown to be capable of potentiating Wnt signalling.
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Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling
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