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PRC2-mediated repression of SMARCA2 predicts EZH2 inhibitor activity in SWI/SNF mutant tumors
Thomas Januario1, Xiaofen Ye1, Russell Bainer2
1Department of Discovery Oncology, Genentech, Inc., South San Francisco, CA 94080.
Abstract:
Subunits of the SWI/SNF chromatin remodeling complex are frequently mutated in human cancers leading to epigenetic dependencies that are therapeutically targetable. The dependency on the polycomb repressive complex (PRC2) and EZH2 represents one such vulnerability in tumors with mutations in the SWI/SNF complex subunit, SNF5; however, whether this vulnerability extends to other SWI/SNF subunit mutations is not well understood. Here we show that a subset of cancers harboring mutations in the SWI/SNF ATPase, SMARCA4, is sensitive to EZH2 inhibition. EZH2 inhibition results in a heterogenous phenotypic response characterized by senescence and/or apoptosis in different models, and also leads to tumor growth inhibition in vivo. Lower expression of the SMARCA2 paralog was associated with cellular sensitivity to EZH2 inhibition in SMARCA4 mutant cancer models, independent of tissue derivation. SMARCA2 is suppressed by PRC2 in sensitive models, and induced SMARCA2 expression can compensate for SMARCA4 and antagonize PRC2 targets. The induction of SMARCA2 in response to EZH2 inhibition is required for apoptosis, but not for growth arrest, through a mechanism involving the derepression of the lysomal protease cathepsin B. Expression of SMARCA2 also delineates EZH2 inhibitor sensitivity for other SWI/SNF complex subunit mutant tumors, including SNF5 and ARID1A mutant cancers. Our data support monitoring SMARCA2 expression as a predictive biomarker for EZH2-targeted therapies in the context of SWI/SNF mutant cancers.
Insights
Tumors with mutations in SWI/SNF subunits like SMARCA4 can be targeted with EZH2 inhibitors. Lower SMARCA2 expression predicts sensitivity, with induced SMARCA2 driving apoptosis and serving as a biomarker for therapy.
Area of Science:
- Oncology
- Epigenetics
- Chromatin Biology
Background:
- SWI/SNF chromatin remodeling complex mutations are common in cancer, creating therapeutic vulnerabilities.
- Polycomb repressive complex 2 (PRC2) and EZH2 inhibition is a known strategy for SNF5-mutant cancers.
- The therapeutic potential of EZH2 inhibition in other SWI/SNF-mutant cancers remains largely unexplored.
Purpose of the Study:
- To investigate the sensitivity of SMARCA4-mutant cancers to EZH2 inhibition.
- To identify biomarkers predicting response to EZH2-targeted therapy in SWI/SNF-mutant cancers.
- To elucidate the molecular mechanisms underlying EZH2 inhibitor sensitivity.
Main Methods:
- Utilized various cancer models with SWI/SNF subunit mutations.
- Administered EZH2 inhibitors and assessed phenotypic responses (senescence, apoptosis).
- Analyzed gene expression, including SMARCA2, PRC2 targets, and cathepsin B.
- Evaluated tumor growth inhibition in vivo.
Main Results:
- A subset of SMARCA4-mutant cancers demonstrated sensitivity to EZH2 inhibition, leading to senescence and/or apoptosis.
- Lower SMARCA2 expression correlated with cellular sensitivity to EZH2 inhibition, independent of tissue type.
- SMARCA2, suppressed by PRC2 in sensitive models, compensates for SMARCA4 loss and antagonizes PRC2 targets.
- SMARCA2 induction is crucial for apoptosis via cathepsin B derepression but not growth arrest.
- SMARCA2 expression also predicts EZH2 inhibitor sensitivity in SNF5 and ARID1A mutant cancers.
Conclusions:
- EZH2 inhibition is a viable therapeutic strategy for a subset of SMARCA4-mutant cancers.
- SMARCA2 expression serves as a predictive biomarker for EZH2 inhibitor sensitivity across various SWI/SNF-mutant cancers.
- Targeting EZH2 offers a promising avenue for treating SWI/SNF-mutant malignancies.
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