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  3. Mapping the landscape of genetic dependencies in chordoma

Mapping the landscape of genetic dependencies in chordoma

  • Nat Commun. 2023 Apr 6;14(1):1933. doi: 10.1038/s41467-023-37593-8.
Tanaz Sharifnia # 1,  Mathias J Wawer # 2 3,  Amy Goodale 2,  Yenarae Lee 2,  Mariya Kazachkova 2 4,  Joshua M Dempster 2,  Sandrine Muller 2,  Joan Levy 5 6,  Daniel M Freed 5,  Josh Sommer 5,  Jérémie Kalfon 2,  Francisca Vazquez 2,  William C Hahn 2 7,  David E Root 2,  Paul A Clemons 2,  Stuart L Schreiber 8 9
Affiliations

Affiliations

  • 1 Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA. tanaz@broadinstitute.org.
  • 2 Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
  • 3 Kojin Therapeutics, Boston, MA, 02210, USA.
  • 4 University of California San Diego, La Jolla, CA, 92093, USA.
  • 5 Chordoma Foundation, Durham, NC, 27702, USA.
  • 6 Melanoma Research Alliance, Washington, D.C., 20005, USA.
  • 7 Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • 8 Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA. stuart_schreiber@harvard.edu.
  • 9 Harvard University, Cambridge, MA, 02138, USA. stuart_schreiber@harvard.edu.
  • # Contributed equally.
PMID: 37024492 DOI: 10.1038/s41467-023-37593-8
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.

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