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The Functional Landscape of Patient-Derived RNF43 Mutations Predicts Sensitivity to Wnt Inhibition.

Publication ,  Journal Article
Yu, J; Yusoff, PAM; Woutersen, DTJ; Goh, P; Harmston, N; Smits, R; Epstein, DM; Virshup, DM; Madan, B
Published in: Cancer Res
December 15, 2020

A subset of Wnt-addicted cancers are sensitive to targeted therapies that block Wnt secretion or receptor engagement. RNF43 loss-of-function (LOF) mutations that increase cell surface Wnt receptor abundance cause sensitivity to Wnt inhibitors. However, it is not clear which of the clinically identified RNF43 mutations affect its function in vivo. We assayed 119 missense and 45 truncating RNF43 mutations found in human cancers using a combination of cell-based reporter assays, genome editing, flow cytometry, and immunofluorescence microscopy. Five common germline variants of RNF43 exhibited wild-type activity. Cancer-associated missense mutations in the RING ubiquitin ligase domain and a subset of mutations in the extracellular domain hyperactivate Wnt/β-catenin signaling through formation of inactive dimers with endogenous RNF43 or ZNRF3. RNF43 C-terminal truncation mutants, including the common G659fs mutant are LOF specifically when endogenous mutations are examined, unlike their behavior in transient transfection assays. Patient-derived xenografts and cell lines with C-terminal truncations showed increased cell surface Frizzled and Wnt/β-catenin signaling and were responsive to porcupine (PORCN) inhibition in vivo, providing clear evidence of RNF43 impairment. Our study provides potential guidelines for patient assignment, as virtually all RNF43 nonsense and frameshift mutations, including those in the C-terminal domain and a large number of patient-associated missense mutations in the RING domain and N-terminal region compromise its activity, and therefore predict response to upstream Wnt inhibitors in cancers without microsatellite instability. This study expands the landscape of actionable RNF43 mutations, extending the benefit of these therapies to additional patients. SIGNIFICANCE: Systematic examination of patient-derived RNF43 mutations identifies rules to guide patient selection, including that truncation or point mutations in well-defined functional domains sensitize cancers to PORCN inhibitors.

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

December 15, 2020

Volume

80

Issue

24

Start / End Page

5619 / 5632

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Wnt Signaling Pathway
  • Ubiquitin-Protein Ligases
  • Protein Multimerization
  • Oncology & Carcinogenesis
  • Neoplasms
  • Mutation
  • Mice, Nude
  • Membrane Proteins
  • Humans
 

Citation

APA
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MLA
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Yu, J., Yusoff, P. A. M., Woutersen, D. T. J., Goh, P., Harmston, N., Smits, R., … Madan, B. (2020). The Functional Landscape of Patient-Derived RNF43 Mutations Predicts Sensitivity to Wnt Inhibition. Cancer Res, 80(24), 5619–5632. https://doi.org/10.1158/0008-5472.CAN-20-0957
Yu, Jia, Permeen A Mohamed Yusoff, Daniëlle T. J. Woutersen, Pamela Goh, Nathan Harmston, Ron Smits, David M. Epstein, David M. Virshup, and Babita Madan. “The Functional Landscape of Patient-Derived RNF43 Mutations Predicts Sensitivity to Wnt Inhibition.Cancer Res 80, no. 24 (December 15, 2020): 5619–32. https://doi.org/10.1158/0008-5472.CAN-20-0957.
Yu J, Yusoff PAM, Woutersen DTJ, Goh P, Harmston N, Smits R, et al. The Functional Landscape of Patient-Derived RNF43 Mutations Predicts Sensitivity to Wnt Inhibition. Cancer Res. 2020 Dec 15;80(24):5619–32.
Yu, Jia, et al. “The Functional Landscape of Patient-Derived RNF43 Mutations Predicts Sensitivity to Wnt Inhibition.Cancer Res, vol. 80, no. 24, Dec. 2020, pp. 5619–32. Pubmed, doi:10.1158/0008-5472.CAN-20-0957.
Yu J, Yusoff PAM, Woutersen DTJ, Goh P, Harmston N, Smits R, Epstein DM, Virshup DM, Madan B. The Functional Landscape of Patient-Derived RNF43 Mutations Predicts Sensitivity to Wnt Inhibition. Cancer Res. 2020 Dec 15;80(24):5619–5632.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

December 15, 2020

Volume

80

Issue

24

Start / End Page

5619 / 5632

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Wnt Signaling Pathway
  • Ubiquitin-Protein Ligases
  • Protein Multimerization
  • Oncology & Carcinogenesis
  • Neoplasms
  • Mutation
  • Mice, Nude
  • Membrane Proteins
  • Humans