Passenger Gene Coamplifications Create Collateral Therapeutic Vulnerabilities in Cancer.

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• DNA amplifications in cancer frequently harbor oncogenes.
• Passenger coamplifications, often overlooked, may also influence cancer progression and treatment.
• Understanding these passenger events is crucial for comprehensive cancer therapy strategies.

Purpose of the Study:

• To investigate if passenger gene coamplifications create collateral therapeutic vulnerabilities.
• To identify specific dependencies arising from passenger coamplifications.
• To explore the therapeutic potential of targeting vulnerabilities created by passenger genes.

Main Methods:

• Analysis of over 3,000 cancer genomes.
• Interrogation of CRISPR-Cas9 loss-of-function screens in over 700 cancer cell lines.
• Proof-of-principle study involving the DEAD-Box Helicase 1 (DDX1) gene, interaction proteomics, and live-cell metabolomics.

Main Results:

• Passenger coamplifications are associated with distinct cancer cell dependency profiles.
• Coamplification of the passenger gene DDX1 enhances dependency on the mTOR pathway.
• DDX1 interacts with tricarboxylic acid (TCA) cycle components, impairing TCA activity and increasing mTORC1 activity.
• Disruption of mTORC1 leads to significant cancer cell death in vitro and in vivo.

Conclusions:

• Structurally linked coamplification of passenger genes and oncogenes can lead to collateral therapeutic vulnerabilities.
• Passenger coamplifications represent a significant, previously underappreciated source of cancer dependencies.
• This principle offers a promising avenue for expanding target discovery in oncology.