Wnt addiction of genetically defined cancers reversed by PORCN inhibition

By Babita Madan, Zhiyuan Ke, N. Harmston, S. Y. Ho, Frois Ashley Oliver, Jenefer Alam, Duraiswamy A. Jeyaraj, V. Pendharkar, Kakaly Ghosh, Isaac Virshup and 9 more. 2015

310 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

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In Molecular Biology

1. Hans Clevers
2. R. Nusse
3. Yanqin Zuo
4. L. Yao
5. Yitian Wang
6. L. Ye
7. Feifei Li
8. F. Yu

Citations in the corpus

• Wnt/β-catenin signaling in cancers and targeted therapies (2021, background): “By the way, ETC131, a similar compound of ETC159, is only used for in vitro assays as a result of its inferior oral bioavailability.(283)”
• Structural basis of WLS/Evi-mediated Wnt transport and secretion (2020, methodology): “The PORCN inhibitor ETC-159 was formulated in DMSO and used at a final concentration of 100 nM as previously described (Madan et al., 2016).”
• Structural model of PORCN illuminates disease-associated variants and drug binding sites (2021, background): “, 2006) to dock the PORCN inhibitors ETC-159 (Madan et al., 2016), Wnt-C59 (Proffitt et al.”
• Wnt/ b -Catenin Signaling, Disease, and Emerging Therapeutic Modalities (2017, background): “In promising experiments, some of these drugs have been shown to inhibit the growth of transplanted or even autochthonous tumors in mousemodels (Madan et al., 2016; Tammela et al., 2017) and a clinical trial for the Porcupine inhibitor LGK974, in patients with several forms of cancer, is ongoing (ht”