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Wnt addiction of genetically defined cancers reversed by PORCN inhibition.

Publication ,  Journal Article
Madan, B; Ke, Z; Harmston, N; Ho, SY; Frois, AO; Alam, J; Jeyaraj, DA; Pendharkar, V; Ghosh, K; Virshup, IH; Manoharan, V; Ong, EHQ; Hill, J ...
Published in: Oncogene
April 28, 2016

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.

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Published In

Oncogene

DOI

EISSN

1476-5594

Publication Date

April 28, 2016

Volume

35

Issue

17

Start / End Page

2197 / 2207

Location

England

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Wnt Signaling Pathway
  • Wnt Proteins
  • Stem Cells
  • Protein Processing, Post-Translational
  • Oncology & Carcinogenesis
  • Mice
  • Membrane Proteins
  • Humans
  • Heterocyclic Compounds, 4 or More Rings
 

Citation

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Madan, B., Ke, Z., Harmston, N., Ho, S. Y., Frois, A. O., Alam, J., … Virshup, D. M. (2016). Wnt addiction of genetically defined cancers reversed by PORCN inhibition. Oncogene, 35(17), 2197–2207. https://doi.org/10.1038/onc.2015.280
Madan, B., Z. Ke, N. Harmston, S. Y. Ho, A. O. Frois, J. Alam, D. A. Jeyaraj, et al. “Wnt addiction of genetically defined cancers reversed by PORCN inhibition.Oncogene 35, no. 17 (April 28, 2016): 2197–2207. https://doi.org/10.1038/onc.2015.280.
Madan B, Ke Z, Harmston N, Ho SY, Frois AO, Alam J, et al. Wnt addiction of genetically defined cancers reversed by PORCN inhibition. Oncogene. 2016 Apr 28;35(17):2197–207.
Madan, B., et al. “Wnt addiction of genetically defined cancers reversed by PORCN inhibition.Oncogene, vol. 35, no. 17, Apr. 2016, pp. 2197–207. Pubmed, doi:10.1038/onc.2015.280.
Madan B, Ke Z, Harmston N, Ho SY, Frois AO, Alam J, Jeyaraj DA, Pendharkar V, Ghosh K, Virshup IH, Manoharan V, Ong EHQ, Sangthongpitag K, Hill J, Petretto E, Keller TH, Lee MA, Matter A, Virshup DM. Wnt addiction of genetically defined cancers reversed by PORCN inhibition. Oncogene. 2016 Apr 28;35(17):2197–2207.

Published In

Oncogene

DOI

EISSN

1476-5594

Publication Date

April 28, 2016

Volume

35

Issue

17

Start / End Page

2197 / 2207

Location

England

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Wnt Signaling Pathway
  • Wnt Proteins
  • Stem Cells
  • Protein Processing, Post-Translational
  • Oncology & Carcinogenesis
  • Mice
  • Membrane Proteins
  • Humans
  • Heterocyclic Compounds, 4 or More Rings