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

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Wnt signaling pathway is crucial in cancer development.
• RNF43 mutations can lead to Wnt pathway dysregulation and cancer.
• Understanding RNF43 mutation impact is vital for targeted therapy selection.

Purpose of the Study:

• To systematically evaluate the functional impact of clinically identified RNF43 mutations.
• To determine which RNF43 mutations confer sensitivity to Wnt inhibitors.
• To establish guidelines for patient stratification for Wnt-targeted therapies.

Main Methods:

• Assayed 119 missense and 45 truncating RNF43 mutations using cell-based assays.
• Utilized genome editing, flow cytometry, and immunofluorescence microscopy.
• Validated findings in patient-derived xenografts and cell lines.

Main Results:

• Cancer-associated missense mutations in the RING domain and extracellular domain hyperactivate Wnt signaling.
• C-terminal truncation mutants, including G659fs, show loss-of-function in endogenous settings.
• RNF43 mutations sensitize cancers to porcupine (PORCN) inhibition, confirmed in vivo.

Conclusions:

• Virtually all nonsense, frameshift, and many missense RNF43 mutations compromise activity.
• These mutations predict response to upstream Wnt inhibitors in specific cancers.
• This study expands the landscape of actionable RNF43 mutations for patient benefit.