ResMap: A community resource for systematic mapping of therapy-persistent residual cancer cell dependencies across...

Area of Science:

• Oncology
• Cancer Biology
• Drug Discovery

Background:

• Relapse in oncogene-driven cancers is often caused by drug-tolerant persister cells.
• Despite extensive research, no therapies specifically targeting persister cells have been approved.
• Developing effective persister-directed therapies is crucial for improving cancer treatment outcomes.

Purpose of the Study:

• To develop ResMap, a standardized framework and dataset for comparing persister vulnerabilities.
• To identify and validate drug targets with anti-persister activity across different cancer models and conditions.
• To accelerate the development of rational persister-directed combination strategies for clinical application.

Main Methods:

• Evaluated 94 compounds targeting 57 candidates in EGFR-mutant and KRAS-G12C lung cancer models.
• Assessed compound efficacy under both normoxic and hypoxic conditions.
• Integrated human cell line essentiality and mouse loss-of-function data for target prioritization.

Main Results:

• Identified 12 conserved anti-persister targets across genotypes and oxygen environments.
• Validated 9 of these targets, with varying specificity against persister cells versus general cytotoxicity.
• Discovered context-specific vulnerabilities, including KRAS-relevant combination targets, some now in clinical testing.

Conclusions:

• ResMap provides a robust platform for systematic persister vulnerability assessment.
• The study identified promising targets for persister-directed therapies, including combination strategies.
• ResMap facilitates community-driven efforts to advance persister-directed treatments to the clinic.