SWI/SNF catalytic subunits’ switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells
Year: 2018
Type: article
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.
Source: Nature Communications
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: Purchase of a PerkinElmer IVIS SpectrumCT Imaging System, G146496267, G1634253349, G3402416433, Targeting Wnt signaling to overcome PARP inhibitor resistance in ovarian cancer, G3925678120, G4490795083, Chromatin basis of cellular senescence and its implication in epithelial ovarian cancer, G6148076407, G6558214066, Targeting EZH2 in CARM1-expressing epithelial ovarian cancer, G8924441417, G9000119698, G9000207185, G9000221700, G9000251175, Advancing Cancer Research through Comprehensive Proteomics and Metabolomics Analyses, Mechanistic basis and therapeutic strategies for ARID1A mutation in ovarian cancer, Consolidated Basic Cancer Research Program
OpenAlex ID: W2895183267