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Catalytic subunits switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells

ABSTRACT: Catalytic subunits switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells

PROVIDER: PRJNA433731 | ENA |

REPOSITORIES: ENA

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Catalytic subunits switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells [RNA-seq]

Project description:The SWI/SNF chromatin remodeling complex is altered in ~20% of human cancers. ARID1A, a component of the SWI/SNF chromatin-remodeling complex, is the most frequently mutated epigenetic regulator in human cancers. Inactivation of the SWI/SNF complex is synthetically lethal with inhibition of EZH2 activity. EZH2 inhibitors are entering clinical trials for specific tumor types with SWI/SNF mutations. However, mechanisms of de novo or acquired 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 ovarian cancer cells.

2019-02-10 | GSE110449 | GEO

Catalytic subunits switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells [ChIP-seq]

2019-02-10 | GSE110448 | GEO

Catalytic subunits switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells [ChIP-seq]

Project description:Catalytic subunits switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells [ChIP-seq]

| PRJNA433733 | ENA

Catalytic subunits switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells [RNA-seq]

Project description:Catalytic subunits switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells [RNA-seq]

| PRJNA433734 | ENA

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

Project description: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.

| S-EPMC6175882 | biostudies-literature

Targeting EZH2 methyltransferase activity in ARID1A mutated cells as a synthetic lethal therapeutic strategy

Project description:ARID1A, an epigentic modifier, is often mutated in ovarian clear cell carcinoma (OCCC). In addition, EZH2 is frequently upregulated in OCCC. Inhibtion of EZH2 with an inhibitor (GSK126) selectively inhibits ARID1A-mutated cells. This study was designed to understand changes in gene expression profiles following EZH2 inhibition or ARID1A restoration. Chromatin remodelers such as ARID1A are frequently mutated in a broad array of cancers. However, targeted cancer therapy based on ARID1A mutation status has not been described. Intriguingly, ARID1A mutated cancers typically lack genomic instability, suggesting significant involvement of epigenetic mechanisms. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A mutated cells. Remarkably, ARID1A mutation status correlated with response to EZH2 inhibitor. Genome-wide profiling revealed antagonistic roles of ARID1A and EZH2 in gene regulation. Further, we identified PIK3IP1 as a direct ARID1A/EZH2 target gene whose upregulation contributes to the observed synthetic lethality in the EZH2 inhibitor treated ARID1A mutated cells. Significantly, EZH2 inhibitor caused the regression of established ARID1A mutated tumors in vivo. Together, this data demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. They indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for ARID1A mutated cancers.

2015-01-20 | E-GEOD-54979 | biostudies-arrayexpress

Catalytic subunits switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-02-10 | GSE110450 | GEO

Targeting EZH2 methyltransferase activity in ARID1A mutated cells as a synthetic lethal therapeutic strategy

2015-01-20 | GSE54979 | GEO

ARID1A-mutated ovarian cancers depend on HDAC6 activity

Project description:ARID1A, encoding a subunit of the SWI/SNF chromatin remodeling complex, is the most mutated epigenetic regulator in human cancers. ARID1A and TP53 mutations are typically mutually exclusive. Therapeutic approaches that correlate with ARID1A mutational status remain a challenge. Here, we show that HDAC6 activity is essential in ARID1A-mutated ovarian cancers. Inhibition of HDAC6 activity using a clinically applicable small molecule inhibitor significantly improved the survival of mice bearing ARID1A-mutated ovarian tumors. This correlated with the suppression of growth and dissemination of ARID1A-mutated, but not wild-type, tumors. The dependence on HDAC6 activity in ARID1A-mutated cells correlated with a direct transcriptional repression of HDAC6 by ARID1A. HDAC6 inhibition selectively promoted apoptosis of ARID1A-mutated cells. HDAC6 directly deacetylated the Lysine 120 residue of p53, a pro-apoptotic post-translational modification. Thus, ARID1A mutation inactivates p53’ apoptotic function by upregulating HDAC6. These results indicate that pharmacological inhibition of HDAC6 is a novel therapeutic strategy involving ARID1A-mutation

2017-07-14 | GSE84405 | GEO

mRNA-seq for HCT116 Parental and ARID1A knockdown cells, mRNA-seq for DLD1 Parental, ARID1A knockdown and ARID1A knockout cells, mRNA-seq for COLO320DM Parental and ARID1A knockdown and ARID1A knockout cells

Project description:The study identifies genes that are regulated by the loss of the chromatin remodeller subunit ARID1A in colorectal cancer cell lines. This gene is frequently mutated in colorectal cancer.

2019-06-11 | E-MTAB-7791 | biostudies-arrayexpress

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