PRC2 loss in MPNST is accompanied by SWI-SNF complex rewiring and sensitization to SMARCA4/2 and BET inhibition

To test our hypothesis, we performed proteogenomic profiling of patient-derived MPNST cell lines stratifying them based on PRC2 status: Loss of Function or Wild Type (LoF or WT) as well as cell fitness assays in response to novel inhibitor of SWI-SNF catalytic activity, FHD-286. Finally, we tested FHD-286 alone and in combination with a BET inhibitor I-BET-762, previously reported to have preferential efficacy in PRC2-deficient MPNST in vivo16.

Our results reveal that PRC2 loss in MPNST is associated with reduction of SWI-SNF protein subunit abundance with higher representation of PBAF exclusive subunits (ARID2, BRD7, PBRM1) together with SMARCD3 in PRC2 LoF. SMARCD3 is also the only SWI-SNF gene significantly upregulated at the mRNA level in PRC2 LoF cell lines. Cell viability and clonogenic assays reveal that the SWI-SNF inhibitor, FHD-286, reduces cell viability of PRC2 LoF MPNST lines at low nanomolar concentrations and disrupts ability to form colonies, while PRC2 WT lines are not as sensitive to treatment.

Finally, evaluating the efficacy of FHD-286 alone and in combination with I-BET-762 in vivo, we observe enhanced activity of the combination regiment compared to single agents in Suz12-deficient murine MPNST xenograft, with 5 mice achieving tumor remission, while in the Suz12 WT arm, the combo was outperformed by I-BET-762 alone. This is the first study conducted to date to demonstrate that SWI-SNF does indeed present as an attractive therapeutic vulnerability in PRC2-deficient MPNSTs.