Related Experiment Videos
SWI/SNF catalytic subunits' switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells
Shuai Wu1, Nail Fatkhutdinov1,2, Takeshi Fukumoto1
1Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, 19104, USA.
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.
Insights
A switch in SWI/SNF subunits (SMARCA4 to SMARCA2) causes resistance to EZH2 inhibitors in ARID1A-mutated cancers. BCL2 inhibition offers a potential therapeutic strategy for these resistant tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- SWI/SNF complex mutations, particularly ARID1A, are synthetically lethal with EZH2 inhibition.
- Mechanisms of de novo resistance to EZH2 inhibitors in SWI/SNF-mutated cancers remain largely unknown.
Purpose of the Study:
- To elucidate the mechanisms driving resistance to EZH2 inhibitors in ARID1A-mutated cancers.
- To identify potential therapeutic strategies to overcome EZH2 inhibitor resistance.
Main Methods:
- Investigated the role of SWI/SNF catalytic subunit switching (SMARCA4 to SMARCA2) in acquired resistance.
- Analyzed the impact of SMARCA4 loss on gene expression, focusing on anti-apoptotic genes.
- Assessed the sensitivity of resistant cells to BCL2 inhibitors (e.g., ABT263).
- Evaluated therapeutic efficacy in preclinical ovarian cancer models.
Main Results:
- A switch from SMARCA4 to SMARCA2 as the catalytic subunit of SWI/SNF drives resistance to EZH2 inhibitors in ARID1A-mutated cells.
- SMARCA4 loss leads to upregulation of anti-apoptotic genes, conferring resistance.
- ARID1A-mutated, EZH2 inhibitor-resistant cells exhibit hypersensitivity to BCL2 inhibitors like ABT263.
- ABT263 monotherapy overcomes EZH2 inhibitor resistance and synergizes with EZH2 inhibitors in vivo.
Conclusions:
- The switch of SWI/SNF catalytic subunits from SMARCA4 to SMARCA2 is a key mechanism of acquired resistance to EZH2 inhibitors.
- BCL2 inhibition, alone or in combination with EZH2 inhibition, presents a promising therapeutic approach for ARID1A-mutated cancers resistant to EZH2 inhibitors.