title: Wnt addiction of genetically defined cancers reversed by PORCN inhibition.
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.
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: B
authors.initials: B
authors.lastname: Madan
authors.affiliation: Experimental Therapeutics Centre, A*STAR, Biopolis, Singapore, Singapore.
authors.forename: Z
authors.initials: Z
authors.lastname: Ke
authors.affiliation: Program in Cardiovascular and Metabolic Disease, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: N
authors.initials: N
authors.lastname: Harmston
authors.affiliation: Experimental Therapeutics Centre, A*STAR, Biopolis, Singapore, Singapore.
authors.forename: S Y
authors.initials: SY
authors.lastname: Ho
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: A O
authors.initials: AO
authors.lastname: Frois
authors.affiliation: Experimental Therapeutics Centre, A*STAR, Biopolis, Singapore, Singapore.
authors.forename: J
authors.initials: J
authors.lastname: Alam
authors.affiliation: Experimental Therapeutics Centre, A*STAR, Biopolis, Singapore, Singapore.
authors.forename: D A
authors.initials: DA
authors.lastname: Jeyaraj
authors.affiliation: Experimental Therapeutics Centre, A*STAR, Biopolis, Singapore, Singapore.
authors.forename: V
authors.initials: V
authors.lastname: Pendharkar
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: K
authors.initials: K
authors.lastname: Ghosh
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: I H
authors.initials: IH
authors.lastname: Virshup
authors.affiliation: Experimental Therapeutics Centre, A*STAR, Biopolis, Singapore, Singapore.
authors.forename: V
authors.initials: V
authors.lastname: Manoharan
authors.affiliation: Experimental Therapeutics Centre, A*STAR, Biopolis, Singapore, Singapore.
authors.forename: E H Q
authors.initials: EH
authors.lastname: Ong
authors.affiliation: Experimental Therapeutics Centre, A*STAR, Biopolis, Singapore, Singapore.
authors.forename: K
authors.initials: K
authors.lastname: Sangthongpitag
authors.affiliation: Experimental Therapeutics Centre, A*STAR, Biopolis, Singapore, Singapore.
authors.forename: J
authors.initials: J
authors.lastname: Hill
authors.affiliation: Program in Cardiovascular and Metabolic Disease, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: E
authors.initials: E
authors.lastname: Petretto
authors.affiliation: Experimental Therapeutics Centre, A*STAR, Biopolis, Singapore, Singapore.
authors.forename: T H
authors.initials: TH
authors.lastname: Keller
authors.affiliation: Experimental Therapeutics Centre, A*STAR, Biopolis, Singapore, Singapore.
authors.forename: M A
authors.initials: MA
authors.lastname: Lee
authors.affiliation: Experimental Therapeutics Centre, A*STAR, Biopolis, Singapore, Singapore.
authors.forename: A
authors.initials: A
authors.lastname: Matter
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.|Department of Pediatrics, Duke University, Durham, NC, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Virshup
mesh_terms: D000217:Acyltransferases; D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage*; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D051379:Mice; D011499:Protein Processing, Post-Translational; D013234:Stem Cells / Q000187:drug effects; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C000620782:ETC-159; D006576:Heterocyclic Compounds, 4 or More Rings; D008565:Membrane Proteins; D051153:Wnt Proteins; D000217:Acyltransferases; C491188:PORCN protein, human