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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Aniline Compounds / administration & dosage
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Cell Line, Tumor
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Chromosomal Proteins, Non-Histone / genetics
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Chromosomal Proteins, Non-Histone / metabolism*
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DNA Helicases / genetics
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DNA Helicases / metabolism
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DNA-Binding Proteins
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Drug Resistance, Neoplasm / drug effects*
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Drug Resistance, Neoplasm / genetics
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Enhancer of Zeste Homolog 2 Protein / antagonists & inhibitors*
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Enhancer of Zeste Homolog 2 Protein / genetics
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Enhancer of Zeste Homolog 2 Protein / metabolism
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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Indoles / administration & dosage
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Indoles / pharmacology*
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Mice, Inbred NOD
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Mice, Knockout
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Mice, SCID
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Mutation
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Ovarian Neoplasms / drug therapy
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Ovarian Neoplasms / genetics
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Ovarian Neoplasms / metabolism
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Pyridones / administration & dosage
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Pyridones / pharmacology*
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Sulfonamides / administration & dosage
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays / methods
Substances
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ARID1A protein, human
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Aniline Compounds
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Chromosomal Proteins, Non-Histone
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DNA-Binding Proteins
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GSK-2816126
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Indoles
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Nuclear Proteins
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Pyridones
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SMARCA2 protein, human
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SWI-SNF-B chromatin-remodeling complex
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Sulfonamides
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Transcription Factors
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EZH2 protein, human
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Enhancer of Zeste Homolog 2 Protein
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SMARCA4 protein, human
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DNA Helicases
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navitoclax