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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Medicinal Chemistry Strategies for the Development of Inhibitors Disrupting β-Catenin's Interactions with Its Nuclear Partners.
TL;DR: In this article , the authors summarize recent advances in biochemical techniques and medicinal chemistry strategies used to identify potent peptide-based and small-molecule inhibitors that directly disrupt β-catenin's interactions with its nuclear binding partners.
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Wnt signaling in liver regeneration, disease, and cancer
Gengyi Zou,Jae Il Park +1 more
TL;DR: The role of Wnt signaling in liver regeneration, precancerous lesion, and liver cancer, and the therapeutic prospects of cancer-specific WNT signaling blockade for liver cancer treatment are discussed.
Posted ContentDOI
Oncogenic Wnt/STOP signaling regulates ribosome biogenesis in vivo
Babita Madan,Nathan Harmston,Gahyathiri Nallan,Alex Montoya,Peter Faull,Enrico Petretto,David M. Virshup +6 more
TL;DR: A central role is identified of Wnt /β-catenin and Wnt/STOP signaling in controlling ribosomal biogenesis, a key driver of cancer proliferation.
Posted ContentDOI
Lineage reversion drives WNT independence in intestinal cancer
Teng Han,Sukanya Goswami,Yang Hu,Fanying Tang,Maria Paz Zafra,Charles J. Murphy,Zhen Cao,Zhen Cao,John T. Poirier,Ekta Khurana,Olivier Elemento,Jaclyn F. Hechtman,Rona Yaeger,Lukas E. Dow +13 more
TL;DR: It is shown that while WNT suppression blocks tumor growth in most organoid and in vivo CRC models, the accumulation of CRC-associated genetic alterations enables drug resistance and WNT-independent growth.
Book ChapterDOI
Diversity of Wnt/β-Catenin Signaling in Head and Neck Cancer: Cancer Stem Cells, Epithelial-to-Mesenchymal Transition, and Tumor Microenvironment
TL;DR: Unraveling the complex circuitries of Wnt/β-catenin signaling will facilitate its effective targeting for HNSCC therapy.
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