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ATF4-Mediated Metabolic Stress Response as a Therapeutic Vulnerability in Chordoma

ABSTRACT: ATF4-Mediated Metabolic Stress Response as a Therapeutic Vulnerability in Chordoma

PROVIDER: PRJNA1152348 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30338526_1.fastq.gz	Fastqsanger.gz
	SRR30338526_2.fastq.gz	Fastqsanger.gz
	SRR30338527_1.fastq.gz	Fastqsanger.gz
	SRR30338527_2.fastq.gz	Fastqsanger.gz
	SRR30338528_1.fastq.gz	Fastqsanger.gz

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ATF4-Mediated Metabolic Stress Response as a Therapeutic Vulnerability in Chordoma [PDX RNA-seq]

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ATF4-Mediated Metabolic Stress Response as a Therapeutic Vulnerability in Chordoma [PDX RNA-seq]

Project description:ATF4-Mediated Metabolic Stress Response as a Therapeutic Vulnerability in Chordoma [PDX RNA-seq]

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ATF4-Mediated Metabolic Stress Response as a Therapeutic Vulnerability in Chordoma

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Project description: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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