VPS37A loss creates CASP8-dependent vulnerability via the MAP3K7-NF-κB-CFLAR axis

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• VPS37A, an ESCRT-I subunit, is crucial for endosomal sorting and autophagy.
• VPS37A is frequently downregulated in various human cancers, often linked to chromosome 8p deletions.
• Early downregulation of VPS37A occurs during tumorigenesis and persists throughout tumor progression.

Purpose of the Study:

• To investigate the functional consequences of VPS37A downregulation in cancer.
• To identify synthetic lethal interactions and therapeutic vulnerabilities associated with VPS37A loss.
• To explore the mechanistic basis for targeting cancer cells with VPS37A deficiency.

Main Methods:

• Integrative analysis of VPS37A gene copy number and CRISPR screening data.
• Investigated the MAP3K7-NF-κB-CFLAR signaling axis and its role in VPS37A-deficient cells.
• Utilized spheroid tumor models to assess therapeutic targeting efficacy.

Main Results:

• VPS37A deficiency, often due to 8p deletion, establishes a synthetic lethal dependency on the MAP3K7-NF-κB-CFLAR axis.
• Targeting this axis induced CASP8-mediated apoptosis and suppressed tumor growth in VPS37A-deficient models.
• This vulnerability relies on ATG8ylated membranes for CASP8 activation, independent of receptor sorting disruption.
• Selective apoptosis induction was observed in spheroid tumors with 8p deletion, even with co-deleted death receptors.

Conclusions:

• VPS37A loss confers a selective vulnerability in cancer cells, particularly those with chromosome 8p deletions.
• The MAP3K7-NF-κB-CFLAR axis represents a promising therapeutic target for cancers with VPS37A downregulation.
• This study provides a mechanistic rationale for developing targeted therapies against VPS37A-deficient tumors.