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Mapping the landscape of genetic dependencies in chordoma

Author

Listed:
  • Tanaz Sharifnia

    (Broad Institute of Harvard and MIT)

  • Mathias J. Wawer

    (Broad Institute of Harvard and MIT
    Kojin Therapeutics)

  • Amy Goodale

    (Broad Institute of Harvard and MIT)

  • Yenarae Lee

    (Broad Institute of Harvard and MIT)

  • Mariya Kazachkova

    (Broad Institute of Harvard and MIT
    University of California San Diego)

  • Joshua M. Dempster

    (Broad Institute of Harvard and MIT)

  • Sandrine Muller

    (Broad Institute of Harvard and MIT)

  • Joan Levy

    (Chordoma Foundation
    Melanoma Research Alliance)

  • Daniel M. Freed

    (Chordoma Foundation)

  • Josh Sommer

    (Chordoma Foundation)

  • Jérémie Kalfon

    (Broad Institute of Harvard and MIT)

  • Francisca Vazquez

    (Broad Institute of Harvard and MIT)

  • William C. Hahn

    (Broad Institute of Harvard and MIT
    Dana-Farber Cancer Institute)

  • David E. Root

    (Broad Institute of Harvard and MIT)

  • Paul A. Clemons

    (Broad Institute of Harvard and MIT)

  • Stuart L. Schreiber

    (Broad Institute of Harvard and MIT
    Harvard University)

Abstract

Identifying the spectrum of genes required for cancer cell survival can reveal essential cancer circuitry and therapeutic targets, but such a map remains incomplete for many cancer types. We apply genome-scale CRISPR-Cas9 loss-of-function screens to map the landscape of selectively essential genes in chordoma, a bone cancer with few validated targets. This approach confirms a known chordoma dependency, TBXT (T; brachyury), and identifies a range of additional dependencies, including PTPN11, ADAR, PRKRA, LUC7L2, SRRM2, SLC2A1, SLC7A5, FANCM, and THAP1. CDK6, SOX9, and EGFR, genes previously implicated in chordoma biology, are also recovered. We find genomic and transcriptomic features that predict specific dependencies, including interferon-stimulated gene expression, which correlates with ADAR dependence and is elevated in chordoma. Validating the therapeutic relevance of dependencies, small-molecule inhibitors of SHP2, encoded by PTPN11, have potent preclinical efficacy against chordoma. Our results generate an emerging map of chordoma dependencies to enable biological and therapeutic hypotheses.

Suggested Citation

  • Tanaz Sharifnia & Mathias J. Wawer & Amy Goodale & Yenarae Lee & Mariya Kazachkova & Joshua M. Dempster & Sandrine Muller & Joan Levy & Daniel M. Freed & Josh Sommer & Jérémie Kalfon & Francisca Vazqu, 2023. "Mapping the landscape of genetic dependencies in chordoma," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37593-8
    DOI: 10.1038/s41467-023-37593-8
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    References listed on IDEAS

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