Mapping the landscape of genetic dependencies in chordoma

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 Vazquez, William C. Hahn, David E. Root, Paul A. Clemons and Stuart L. Schreiber ()
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Tanaz Sharifnia: Broad Institute of Harvard and MIT
Mathias J. Wawer: Broad Institute of Harvard and MIT
Amy Goodale: Broad Institute of Harvard and MIT
Yenarae Lee: Broad Institute of Harvard and MIT
Mariya Kazachkova: Broad Institute of Harvard and MIT
Joshua M. Dempster: Broad Institute of Harvard and MIT
Sandrine Muller: Broad Institute of Harvard and MIT
Joan Levy: Chordoma Foundation
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
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

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37593-8

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