SMARCE1 deficiency generates a targetable mSWI/SNF dependency in clear cell meningioma

SMARCE1 loss destabilizes the canonical BAF complex and increases the formation of BRD9-containing non-canonical (ncBAF) complexes. SMARCE1-deficient cells, which are a model for clear cell meningioma, are sensitive to ncBAF complex inhibition. Mammalian SWI/SNF (mSWI/SNF) ATP-dependent chromatin remodeling complexes establish and maintain chromatin accessibility and gene expression, and are frequently perturbed in cancer. Clear cell meningioma (CCM), an aggressive tumor of the central nervous system, is uniformly driven by loss of SMARCE1, an integral subunit of the mSWI/SNF core. Here, we identify a structural role for SMARCE1 in selectively stabilizing the canonical BAF (cBAF) complex core-ATPase module interaction. In CCM, cBAF complexes fail to stabilize on chromatin, reducing enhancer accessibility, and residual core module components increase the formation of BRD9-containing non-canonical BAF (ncBAF) complexes. Combined attenuation of cBAF function and increased ncBAF complex activity generates the CCM-specific gene expression signature, which is distinct from that of NF2-mutated meningiomas. Importantly, SMARCE1-deficient cells exhibit heightened sensitivity to small-molecule inhibition of ncBAF complexes. These data inform the function of a previously elusive SWI/SNF subunit and suggest potential therapeutic approaches for intractable SMARCE1-deficient CCM tumors.

Automated summary

SMARCE1 loss destabilizes the canonical BAF complex and increases the formation of BRD9-containing non-canonical (ncBAF) complexes. This study reveals a structural role for SMARCE1 in stabilizing the canonical BAF complex on chromatin and identifies potential therapeutic approaches for SMARCE1-deficient clear cell meningioma tumors.