Paralog knockout profiling identifies DUSP4 and DUSP6 as a digenic dependence in MAPK pathway-driven cancers

Area of Science:

• Genomics
• Cancer Biology
• Drug Discovery

Background:

• Single-gene studies have limitations in identifying cancer vulnerabilities.
• Functional redundancy between genes can mask therapeutic targets.
• Understanding digenic dependencies is crucial for novel cancer treatments.

Purpose of the Study:

• To identify digenic dependencies masked by gene redundancy.
• To explore the impact of dual gene inactivation on cell viability.
• To uncover new therapeutic targets in cancer.

Main Methods:

• Developed a CRISPR paralog targeting library.
• Investigated viability effects of disrupting 3,284 genes, 5,065 paralog pairs, and 815 paralog families.
• Utilized multigene perturbation technology.

Main Results:

• Identified dual inactivation of DUSP4 and DUSP6 selectively impairs growth in NRAS and BRAF mutant cells.
• Observed hyperactivation of MAPK signaling upon DUSP4/DUSP6 inactivation.
• Found that cells resistant to MAPK inhibitors are cross-sensitized to DUSP4/DUSP6 perturbations.

Conclusions:

• Multigene perturbation reveals previously unrecognized digenic vulnerabilities.
• DUSP4 and DUSP6 inactivation represents a potential therapeutic strategy for specific cancer types.
• This approach can overcome resistance mechanisms in MAPK-targeted therapies.