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 applied 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 confirmed a known chordoma dependency, TBXT (T; brachyury), and identified 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, were also recovered. We found 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, had potent preclinical efficacy against chordoma. Our results generate an emerging map of chordoma dependencies to enable biological and therapeutic hypotheses.
Competing Interest Statement
M.J.W. is an employee and shareholder of Kojin Therapeutics. F.V. receives research support from Novo Ventures. D.E.R. receives research funding from members of the Functional Genomics Consortium (Abbvie, Bristol-Myers Squibb, Jannsen, Merck, Vir), and is a director of Addgene, Inc. W.C.H. is a consultant for ThermoFisher, Solasta, MPM Capital, Frontier Medicines, Tyra Biosciences, RAPPTA Therapeutics, KSQ Therapeutics, Jubilant Therapeutics, Function Oncology and Calyx. P.A.C. is an advisor to Pfizer, Inc., and Belharra Therapeutics. S.L.S. serves on the Board of Directors of the Genomics Institute of the Novartis Research Foundation ("GNF"); is a shareholder and serves on the Board of Directors of Jnana Therapeutics; is a shareholder of Forma Therapeutics; is a shareholder and advises Kojin Therapeutics, Kisbee Therapeutics, Decibel Therapeutics and Eikonizo Therapeutics; serves on the Scientific Advisory Boards of Eisai Co., Ltd., Ono Pharma Foundation, Exo Therapeutics and F-Prime Capital Partners; and is a Novartis Faculty Scholar. All other authors declare no competing interests.