Spatially-resolved Photoproximity Profiling of MYC Identifies a MYC-BAF Liability in Cancer Cells

Area of Science:

• Oncology
• Molecular Biology
• Proteomics

Background:

• Aberrant expression of the c-MYC transcription factor drives proliferation in many human cancers.
• Understanding MYC's protein interactions within its regulatory complexes is crucial for identifying therapeutic targets.
• Previous methods have faced challenges in defining context-specific MYC interactors due to its complex structure and interactions.

Purpose of the Study:

• To develop and apply a novel method for mapping MYC-centered protein complex topologies within cells.
• To identify context-dependent MYC interactors in disease-relevant models.
• To explore the therapeutic potential of targeting MYC-protein interactions in MYC-driven cancers.

Main Methods:

• Development of a matched pair of photoproximity probes for intracellular mapping.
• Application of spatially resolved, intracellular photoproximity (siPROX) profiling coupled with quantitative proteomics.
• Analysis of MYC interactomes across temporal, spatial, and disease-relevant contexts, including inhibitor treatments.

Main Results:

• siPROX successfully mapped known MYC interactors and revealed dynamic remodeling of transcriptional regulators upon inhibitor treatment.
• The study identified persistent interactions with BAF complex members (e.g., PBRM1, SMARCC1) even with bromodomain inhibition.
• Inhibition of BAF complex ATPase activity (SMARCA2/4) led to decreased MYC levels, reduced MYC-dependent transcription, and impaired cancer cell growth.

Conclusions:

• The siPROX technique is effective for identifying spatially resolved, dynamic transcription factor interactors.
• MYC interactions with the BAF complex represent a targetable vulnerability in MYC-driven cancers.
• Targeting MYC-BAF interactions offers a potential strategy to regulate MYC-dependent transcription and proliferation.