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 Pathway in the Development and Progression of Colorectal Cancer
TL;DR: The Wnt/β-catenin signaling pathway is a growth control pathway involved in various biological processes as well as the development and progression of cancer as discussed by the authors , which plays a crucial role in cancerrelated processes such as cancer stem cell propagation, angiogenesis, epithelial-mesenchymal transition (EMT), chemoresistance, and metastasis.
Peer Review
HCC incidence is decreasing in Korea but increasing in elderly
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Wnt Signaling in Brain Tumors: A Challenging Therapeutic Target
TL;DR: In this article , the main molecular mechanism through which the Wnt pathway exerts its intracellular effects, with a specific focus on brain development and brain tumors, and how Wnt interacts with the surrounding brain environment.
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The Structure-Activity Relationship Study of Dicarboximide-phenylpyridine Conjugates as Inhibitors of Wnt Signaling Pathway
Hongna Wu,Jun Wu,Qin Tong,Xu Lian,Zhongwen Li,Baojie Guo,Jie Hao,Li Tianlei,Wenxuan Zhang,Song Wu +9 more
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Role of non‑coding RNA intertwined with the Wnt/β‑catenin signaling pathway in endometrial cancer (Review)
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