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Nat Commun. 2018 Oct 8;9(1):4116. doi: 10.1038/s41467-018-06656-6.

SWI/SNF catalytic subunits' switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells.

Author information

1
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, 19104, USA.
2
Kazan Federal University, Kazan, 420008, Russia.
3
Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA, 19104, USA.
4
Proteomics and Metabolomics Facility, The Wistar Institute, Philadelphia, PA, 19104, USA.
5
Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
6
Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, 19104, USA.
7
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, 19104, USA. rzhang@wistar.org.

Abstract

Inactivation of the subunits of SWI/SNF complex such as ARID1A is synthetically lethal with inhibition of EZH2 activity. However, mechanisms of de novo resistance to EZH2 inhibitors in cancers with inactivating SWI/SNF mutations are unknown. Here we show that the switch of the SWI/SNF catalytic subunits from SMARCA4 to SMARCA2 drives resistance to EZH2 inhibitors in ARID1A-mutated cells. SMARCA4 loss upregulates anti-apoptotic genes in the EZH2 inhibitor-resistant cells. EZH2 inhibitor-resistant ARID1A-mutated cells are hypersensitive to BCL2 inhibitors such as ABT263. ABT263 is sufficient to overcome resistance to an EZH2 inhibitor. In addition, ABT263 synergizes with an EZH2 inhibitor in vivo in ARID1A-inactivated ovarian tumor mouse models. Together, these data establish that the switch of the SWI/SNF catalytic subunits from SMARCA4 to SMARCA2 underlies the acquired resistance to EZH2 inhibitors. They suggest BCL2 inhibition alone or in combination with EZH2 inhibition represents urgently needed therapeutic strategy for ARID1A-mutated cancers.

PMID:
30297712
PMCID:
PMC6175882
DOI:
10.1038/s41467-018-06656-6
[Indexed for MEDLINE]
Free PMC Article

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