Mapping the landscape of genetic dependencies in chordoma

Area of Science:

• Oncology
• Genomics
• Cancer Biology

Background:

• Identifying genes critical for cancer cell survival is key to understanding cancer circuitry and finding therapeutic targets.
• Chordoma, a bone cancer, has a limited number of validated therapeutic targets, necessitating further research into its essential genetic dependencies.

Purpose of the Study:

• To map the landscape of selectively essential genes in chordoma using genome-scale CRISPR-Cas9 loss-of-function screens.
• To identify novel therapeutic targets and understand the genetic dependencies driving chordoma.
• To correlate genomic and transcriptomic features with specific gene dependencies.

Main Methods:

• Genome-scale CRISPR-Cas9 loss-of-function screens were employed to identify essential genes in chordoma.
• Bioinformatic analyses were used to correlate genomic and transcriptomic data with identified gene dependencies.
• Preclinical efficacy of small-molecule inhibitors targeting identified dependencies was evaluated.

Main Results:

• The study confirmed TBXT (T; brachyury) as a chordoma dependency and identified new dependencies including PTPN11, ADAR, PRKRA, LUC7L2, SRRM2, SLC2A1, SLC7A5, FANCM, and THAP1.
• Previously implicated genes like CDK6, SOX9, and EGFR were also recovered.
• Interferon-stimulated gene expression was found to correlate with ADAR dependence and is elevated in chordoma.
• Small-molecule inhibitors targeting SHP2 (PTPN11) demonstrated potent preclinical efficacy.

Conclusions:

• The research provides a map of chordoma dependencies, offering new avenues for biological and therapeutic exploration.
• PTPN11, encoding SHP2, is a validated therapeutic target for chordoma, with inhibitors showing significant preclinical activity.
• Understanding gene dependencies and their correlation with molecular features can guide precision medicine approaches in chordoma treatment.