Cohesin mutations are synthetic lethal with stimulation of WNT signaling

Area of Science:

• Cancer Biology
• Molecular Oncology
• Genetics

Background:

• Mutations in cohesin complex genes are prevalent in various cancers.
• These mutations can present unique therapeutic vulnerabilities.
• The cohesin complex plays a crucial role in genome stability and gene regulation.

Purpose of the Study:

• To identify synthetic lethal interactions with cohesin subunit mutations.
• To explore the therapeutic potential of targeting vulnerabilities in cohesin-mutant cancers.
• To investigate the role of Wnt signaling in cohesin-mutant oncogenesis.

Main Methods:

• Generated isogenic cell lines with cohesin subunit deletions (SMC3, RAD21, STAG2).
• Screened 3009 FDA-approved compounds for synthetic lethality.
• Utilized beta-catenin stabilization assays and Wnt-responsive gene expression analysis.
• Employed zebrafish models with mutations in cohesin subunits (stag2b, rad21).

Main Results:

• Identified compounds affecting transcription, DNA repair, and cell cycle.
• Discovered GSK3 inhibitors as potent sensitizers in cohesin-mutant cells.
• Demonstrated beta-catenin stabilization as the mechanism for GSK3 inhibitor sensitivity.
• Observed enhanced Wnt signaling in STAG2-mutant leukemia cells and zebrafish models.

Conclusions:

• Cohesin mutations may promote cancer by enhancing Wnt signaling.
• Targeting the Wnt pathway represents a potential therapeutic strategy for cohesin-mutant cancers.
• GSK3 inhibition offers a novel approach for treating these malignancies.