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RNF43 G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition

Author

Listed:
  • Lishan Fang

    (Harvard Medical School
    Broad Institute of MIT and Harvard
    Sun Yat-sen University)

  • Dane Ford-Roshon

    (Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Max Russo

    (Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Casey O’Brien

    (Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Xiaozhe Xiong

    (Boston Children’s Hospital
    Blavatnik Institute, Harvard Medical School)

  • Carino Gurjao

    (Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Maximilien Grandclaudon

    (Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Srivatsan Raghavan

    (Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Steven M. Corsello

    (Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Steven A. Carr

    (Broad Institute of MIT and Harvard)

  • Namrata D. Udeshi

    (Broad Institute of MIT and Harvard)

  • James Berstler

    (Broad Institute of MIT and Harvard)

  • Ewa Sicinska

    (Harvard Medical School)

  • Kimmie Ng

    (Harvard Medical School)

  • Marios Giannakis

    (Harvard Medical School
    Broad Institute of MIT and Harvard)

Abstract

The RNF43_p.G659fs mutation occurs frequently in colorectal cancer, but its function remains poorly understood and there are no specific therapies directed against this alteration. In this study, we find that RNF43_p.G659fs promotes cell growth independent of Wnt signaling. We perform a drug repurposing library screen and discover that cells with RNF43_p.G659 mutations are selectively killed by inhibition of PI3K signaling. PI3K/mTOR inhibitors yield promising antitumor activity in RNF43659mut isogenic cell lines and xenograft models, as well as in patient-derived organoids harboring RNF43_p.G659fs mutations. We find that RNF43659mut binds p85 leading to increased PI3K signaling through p85 ubiquitination and degradation. Additionally, RNA-sequencing of RNF43659mut isogenic cells reveals decreased interferon response gene expression, that is reversed by PI3K/mTOR inhibition, suggesting that RNF43659mut may alter tumor immunity. Our findings suggest a therapeutic application for PI3K/mTOR inhibitors in treating RNF43_p.G659fs mutant cancers.

Suggested Citation

  • Lishan Fang & Dane Ford-Roshon & Max Russo & Casey O’Brien & Xiaozhe Xiong & Carino Gurjao & Maximilien Grandclaudon & Srivatsan Raghavan & Steven M. Corsello & Steven A. Carr & Namrata D. Udeshi & Ja, 2022. "RNF43 G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30794-7
    DOI: 10.1038/s41467-022-30794-7
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