PRC2 loss in MPNST is accompanied by SWI/SNF complex rewiring and sensitization to SMARCA2/4 and BET inhibition in vivo.

Authors

Kirill Miachin, Marc Alard Morgan, Guangfeng Wang, Jacquelyn A Myers, John J Navarro, Joanna Lempiäinen, Xingyu Liu, Mingzhou Zhou, Kuangying Yang, Diana Akinyi Odhiambo, David W W Hill, Charles W M Roberts, Angela C Hirbe, Benjamin A Garcia

Published in

Molecular & cellular proteomics : MCP. Pages 101662. Sep 18, 2026. Epub Sep 18, 2026.

Abstract

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive sarcomas of peripheral nerve sheath that frequently arise in patients with neurofibromatosis type 1 (NF1) and currently have no approved targeted treatment. Loss of Polycomb Repressive Complex 2 (PRC2) activity, through inactivating mutations in SUZ12 or EED, occurs in 50 to 80% of NF1-associated MPNSTs, leads to depletion of H3K27me3 in cells, global epigenetic dysregulation, and serves as an indicator of poor clinical outcomes. SWI/SNF (BAF) complexes are ATPase-driven chromatin remodelers essential for orderly transcriptional activity in cells. Because PRC2 and SWI/SNF enforce functionally antagonistic effects on chromatin, we hypothesized that PRC2-deficient MPNSTs undergo alterations in the SWI/SNF complex that create a therapeutic vulnerability to SWI/SNF inhibition. We performed integrated proteogenomic profiling of patient-derived MPNST cell lines stratified by PRC2 status: Loss of Function (LoF) or Wild Type (WT). We found that PRC2 loss in MPNST was associated with broad reduction in global SWI/SNF protein abundance, recurrent enrichment of SMARCD3 in SMARCA4-containing complexes, and context-dependent enrichment of DPF3 and PBAF-specific subunits. ChIP-seq analyses showed redistribution of cBAF and PBAF chromatin occupancy in PRC2 LoF models followed by concordant increases in H3K27ac signal and gene expression. Cell fitness assays revealed that the SWI/SNF ATPase inhibitor, FHD-286, reduced cell viability in PRC2 LoF MPNST lines at low nanomolar concentrations and disrupted the colony forming ability, while PRC2 WT cell lines were less sensitive to treatment. Finally, evaluating the efficacy of FHD-286 alone, and in combination with I-BET-762, in an isogenic PRC2 loss murine allograft MPNST model, we observed enhanced efficacy of the combination regimen compared to either single agent in the Suz12 KO arm, while in the Suz12 WT arm, the combo was outperformed by I-BET-762 alone. Together, our findings indicate that PRC2 loss in MPNST is accompanied by selective subunit remodeling and genomic redistribution of SWI/SNF complexes and support SWI/SNF ATPase inhibition, alone and in combination with BET inhibition, as an attractive therapeutic strategy for PRC2-deficient MPNSTs.

PMID:
42759702
Bibliographic data and abstract were imported from PubMed on 19 Sep 2026.

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