Shifted assembly and function of mSWI/SNF family subcomplexes underlie targetable dependencies in dedifferentiated endometrial carcinomas

St. Laurent, J. D.; Xu, G. D.; Ying, A. W.; Gokbayrak, B.; Patil, A.; Paulo, J. A.; Cervantes, K. S.; Chen, S.; Feng, W. W.; Sankar, A.; Same Guerra, D. D.; Qi, J.; Neel, D. S.; Hornick, J. L.; Kolin, D. L.; Gygi, S.; Huntsman, D. G.; Wang, Y.; Kadoch, C.

doi:10.1101/2025.10.13.681937

bioRxiv · 10.1101/2025.10.13.681937

Shifted assembly and function of mSWI/SNF family subcomplexes underlie targetable dependencies in dedifferentiated endometrial carcinomas

St. Laurent, J. D.·Xu, G. D.·Ying, A. W.·Gokbayrak, B.·Patil, A.·Paulo, J. A.·Cervantes, K. S.·Chen, S.·Feng, W. W.·Sankar, A.·Same Guerra, D. D.·Qi, J.·Neel, D. S.·Hornick, J. L.·Kolin, D. L.·Gygi, S.·Huntsman, D. G.·Wang, Y.·Kadoch, C.

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Abstract

The mammalian SWI/SNF (mSWI/SNF) family of chromatin remodelers govern cell type-specific chromatin accessibility and gene expression and assemble as three distinct complexes: canonical BAF (cBAF), Polybromo-associated BAF (PBAF), and non-canonical BAF (ncBAF). ARID1A and ARID1B are paralog subunits that specifically nucleate the assembly of cBAF complexes and are frequently co-mutated in highly aggressive dedifferentiated/undifferentiated endometrial carcinomas (DDEC/UECs). Here, in cellular models and primary human tumors, we find that ARID1A/B deficiency-mediated cBAF loss results in increased ncBAF and PBAF biochemical abundance and chromatin-level functions to maintain the DDEC oncogenic state. Further, treatment with clinical-grade SMARCA4/2 ATPase inhibitors markedly attenuates DDEC cell proliferation and tumor growth in vivo and synergizes with carboplatin-based chemotherapy to extend survival. These findings reveal the oncogenic contributions of shifted mSWI/SNF family complex stoichiometry and resulting gene regulatory dysregulation and suggest therapeutic utility of mSWI/SNF small molecule inhibitors in DDEC/UEC and other cBAF-disrupted cancer types.

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St. Laurent, J. D., Xu, G. D., Ying, A. W., Gokbayrak, B., Patil, A., Paulo, J. A., Cervantes, K. S., Chen, S., Feng, W. W., Sankar, A., Same Guerra, D. D., Qi, J., Neel, D. S., Hornick, J. L., Kolin, D. L., Gygi, S., Huntsman, D. G., Wang, Y., Kadoch, C.. 2025-10-14. Shifted assembly and function of mSWI/SNF family subcomplexes underlie targetable dependencies in dedifferentiated endometrial carcinomas. https://doi.org/10.1101/2025.10.13.681937

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