ArticleProceedings of the National Academy of Sciences of the United States of America2017
PRC2-mediated repression of SMARCA2 predicts EZH2 inhibitor activity in SWI/SNF mutant tumors.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 102 citations in OpenAlex.
- Tazemetostat, an EZH2 inhibitor, in solid tumors harboring SWI/SNF alterations: a phase II basket study.Nature communications · 2026Trial
- Mutant Huntingtin disrupts neurogenic and astroglial programs via the EZH2-Let-7g-LIN28 axis with rescue by epigenetic modulators.Cell death and differentiation · 2026Article
- EZH2 Regulates the Proliferation-Senescence Balance and Tumor-Stromal Signaling in Lung Adenocarcinoma.International journal of molecular sciences · 2026Article
- Mapping of the hSOX10 Proximal Protein Interactome in Human Melanoma.Journal of proteome research · 2026Article
- Targeting the CHD3 chromatin remodeler exploits a synthetic lethal vulnerability in dual SMARCA4/SMARCA2-deficient cancers via derepression of PARD3B.NPJ precision oncology · 2026Article
- Tumor suppressors LKB1 and SMARCA4 functionally interact to regulate gene expression across diverse biological processes in lung cancer.Frontiers in cell and developmental biology · 2026Article
- Stable disease after multimodal treatment of SMARCA4-deficient undifferentiated tumor concurrently involving the stomach and mediastinum: a case report.Frontiers in oncology · 2026Article
- Mapping of the hSOX10 protein interactome in human melanoma.bioRxiv : the preprint server for biology · 2025Article
- Safety and efficacy of HH2853, a novel EZH1/2 dual inhibitor, in patients with refractory solid tumours or non-Hodgkin lymphomas: a phase I study.EClinicalMedicine · 2025Article
- Review
- Small cell lung carcinoma with YAP1 expression and SMARCA4-deficient undifferentiated tumors.Translational cancer research · 2025Article
- Tumor-agnostic therapy: a potential therapeutic approach for SMARCA4-deficient malignancies.Therapeutic advances in medical oncology · 2025Review
- Hypermethylation of CDKN2A CpG island drives resistance to PRC2 inhibitors in SWI/SNF loss-of-function tumors.Cell death & disease · 2024Article
- Epigenetic and Immune Profile Characteristics in Sinonasal Undifferentiated Carcinoma.Cancer medicine · 2024Article
- Bivalent chromatin accommodates survivin and BRG1/SWI complex to activate DNA damage response in CD4Cell communication and signaling : CCS · 2024Article
- Comprehensive Target Engagement by the EZH2 Inhibitor Tulmimetostat Allows for Targeting of ARID1A Mutant Cancers.Cancer research · 2024Article
- SMARCA4 controls state plasticity in small cell lung cancer through regulation of neuroendocrine transcription factors and REST splicing.Journal of hematology & oncology · 2024Article
- Overcoming Clinical Resistance to EZH2 Inhibition Using Rational Epigenetic Combination Therapy.Cancer discovery · 2024Article
- Treatment of Thoracic SMARCA4-Deficient Undifferentiated Tumors: Where We Are and Where We Will Go.International journal of molecular sciences · 2024Review
- Case report: Aggressive NSCLC with partial BRG-1 deficiency and KRAS G12C mutation: a case study and treatment challenges.Frontiers in oncology · 2024Article
Corrections and comments
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9 authors.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.