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Overcoming clinical resistance to EZH2 inhibition using rational epigenetic combination therapy

ABSTRACT: Recent work has revealed essential epigenetic dependencies in many cancers. Based on the functional antagonism between BAF/SWI/SNF and Polycomb repressive complex 2 chromatin remodeling in SMARCB1-deficient sarcomas, we and colleagues recently completed the clinical trial of the EZH2 inhibitor tazemetostat, leading to its FDA approval. However, the principles of response and resistance to epigenetic therapy in general and tazemetostat in particular remain unknown. Using comparative functional genomics of clinical tumor specimens and diverse experimental model systems, we have now defined molecular mechanisms of resistance to tazemetostat in epithelioid sarcomas and rhabdoid tumors. We found distinct classes of acquired mutations that converge on the RB/E2F axis and decouple EZH2 inhibition-dependent tumor cell differentiation and cell cycle control. This allows tumor cells to escape tazemetostat-induced G1 arrest, despite an active transcriptional response, and provides a general mechanism for effective EZH2 inhibitor therapy. Thus, we develop combination strategies to circumvent tazemetostat resistance by using cell cycle bypass and synthetic lethal targeting, and provide prospective biomarkers for future therapy stratification. This offers a paradigm for rational epigenetic combination therapy suitable for immediate translation to clinical trials for patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE213845 | GEO | 2023/02/07

REPOSITORIES: GEO

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CUT&RUN profiling of histone H3K27ac and H3K27me3 localization after pharmacological inhibition of EZH2 and BET proteins

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Combined inhibition of EZH2 and degradation of Ikaros has synergistic effects in germinal center B-cell diffuse large B-cell lymphoma [RNA-seq]

Project description:To explore the therapeutic opportunities to enhance the clinical efficacy of EZH2 inhibitors in treating diffuse large B-cell lymphoma (DLBCL), a genome-wide drug sensitizing CRISPR/Cas9 screen was conducted in the presence of tazemetostat. We found that the loss of IKZF1 or IKZF3 augmented the potency of tazemetostat on DLBCL. Treating cells with lenalidomide, an immunomodulatory drug that degrades IKZF1 and IKZF3, in combination with tazemetostat, recapitulated the effects observed in the drug sensitizing screen. The combined drug treatment showed even higher synergistic effects, by triggering either cell cycle arrest or apoptosis, on a broader range of DLBCL cell lines, regardless of EZH2 mutation status. RNAseq analysis revealed strong upregulation of the interferon signaling and antiviral immune response signatures. Gene expression of key factors such as IRF7 and DDX58 were highly induced in cells treated with lenalidomide and tazemetostat, with a concomitant enrichment of H3K27 acetylation at their promoters as delineated in ChIPseq and ChIP qPCR analyses. Furthermore, transcriptome analysis and immunofluorescence staining demonstrated pronounced expression of a wide range of endogenous retroviruses (ERVs), with significant overlaps between the upregulated ERV loci and well-defined H3K27me3 enriched regions in EZH2-mutant lymphoma cell lines. Our data underscore the synergistic interplay between lenalidomide and tazemetostat on modulating epigenetic changes, resulting in upregulation of the interferon response and de-repression of ERVs, and ultimately to reduced growth of GCB-type DLBCL.

2021-06-24 | GSE151607 | GEO

Combined inhibition of EZH2 and degradation of Ikaros has synergistic effects in germinal center B-cell diffuse large B-cell lymphoma [ChIP-seq]

2021-06-24 | GSE152028 | GEO

Metronomic doxorubicin blocks HIF-1α-mediated responses in sarcomas and augments the effects of anti-VEGF-A therapy

Project description:Increased levels of hypoxia and hypoxia inducible factor 1α (HIF-1α) in human sarcomas correlate with tumor progression and radiation resistance. Prolonged anti-angiogenic therapy of tumors can delay tumor growth but may also increase hypoxia and HIF-1α activity. In our recent clinical trial, treatment with the anti-vascular endothelial growth factor A (VEGF-A) antibody, bevacizumab, followed by a combination of bevacizumab and radiation led to near complete necrosis in nearly half of sarcomas. Gene set enrichment analysis of microarrays from pre-treatment biopsies found the Gene Ontology category “Response to hypoxia” was upregulated in poor responders, and hierarchical clustering based on 140 hypoxia-responsive genes separated poor responders from good responders. The most commonly used chemotherapeutic drug for sarcomas, doxorubicin (Dox), was recently found to block HIF-1α binding to DNA at low metronomic doses. We thus examined Dox treatment in 4 sarcoma cell lines, and found Dox at low concentrations (1-10 uM) blocked HIF-1α induction of VEGF-A by 84-97%, while inhibition of other HIF-1α-target genes including CA9, c-Met and FOXM1 was variable. HT1080 sarcoma xenografts had increased hypoxia and/or HIF-1α activity with increasing tumor size and with anti-VEGF receptor antibody (DC101) treatment. Combining DC101 and metronomic Dox had a synergistic effect in suppressing growth of HT1080 xenografts, primarily via induction of tumor endothelial cell apoptosis. In conclusion, sarcomas respond to increased hypoxia by expressing HIF-1α-target genes which may promote resistance to anti-angiogenic and other therapies. Metronomic Dox can block HIF-1α activation of target genes and works synergistically with anti-VEGF therapy to inhibit sarcomas. Pre-treatment biopsies were collected from 16 human sarcoma. The gene expression analysis was performed using Illumina platform.

2011-08-29 | E-GEOD-31715 | biostudies-arrayexpress

Rb and p53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance

Project description:Prostate cancer relapsing from antiandrogen therapies can exhibit variant histology with altered lineage marker expression, suggesting lineage plasticity facilitates therapeutic resistance. Mechanisms underlying prostate cancer lineage plasticity are unknown, and relevant experimental models are needed. We demonstrate Rb1 loss facilitates lineage plasticity and metastasis of prostate adenocarcinoma initiated by Pten mutation in the mouse. Additional loss of Trp53 causes resistance to antiandrogen therapy. Gene expression profiling indicates mouse tumors are comparable to human prostate cancer neuroendocrine variants; both mouse and human tumors exhibit increased expression of epigenetic reprogramming factors like Ezh2 and Sox2. Clinically relevant Ezh2 inhibitors restore androgen receptor expression and sensitivity to antiandrogen therapy. These findings uncover genetic mutations enabling prostate cancer progression, identify mouse models for studying prostate cancer lineage plasticity, and suggest an epigenetic approach for extending clinical responses to antiandrogen therapy.

2017-02-24 | GSE90891 | GEO

EZH2 inhibition sensitizes IDH1R132H mutant gliomas to Panobinostat

Project description:Isocitrate Dehydrogenase-1 (IDH1) is commonly mutated in lower grade diffuse gliomas. The IDH1R132H mutation is an important diagnostic tool for tumor diagnosis and prognosis, however its role in glioma development, and its impact on response to therapy, is not fully understood. We developed a murine model of proneural IDH1R132H mutated glioma that shows elevated production of 2-Hydroxyglutarate (2-HG) and increased tri-methylation of lysine residue K27 on histone H3 (H3K27me3) compared to IDH1 wild-type tumors. We found that using Tazemetostat to inhibit the methyltransferase for H3K27, Enhancer of Zeste 2 (EZH2), reduced H3K27me3 levels and increased acetylation on H3K27. We also found that, although the histone deacetylase inhibitor (HDACi) Panobinostat was less cytotoxic in IDH1R132H mutated cells (either isolated from murine glioma or oligodendrocyte progenitor cells infected in vitro with a retrovirus expressing IDH1R132H) compared to IDH1-wildtype cells, co-treatment with Tazemetostat is synergistic in both mutant and wildtype models. These findings indicate a novel therapeutic strategy for IDH1-mutated gliomas that targets the specific epigenetic alteration in these tumors.

2023-07-12 | GSE236815 | GEO

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

Three different in vivo models of synovial sarcoma (xenograft: Fuji; PDX: CTG-0331 and CTG-0771) treated with or without the indicated dose of the EZH2 inhibitor, tazemetostat

Project description:The catalytic activities of covalent and ATP-dependent chromatin remodeling are central to regulating the conformational state of chromatin and the resultant transcriptional output. The enzymes that catalyze these activities are often contained within multiprotein complexes in nature. Two such multiprotein complexes, the polycomb repressive complex 2 (PRC2) methyltransferase and the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeler have been reported to act in opposition to each other during development and homeostasis. An imbalance in their activities induced by mutations/deletions in complex members (e.g. SMARCB1) has been suggested to be a pathogenic mechanism in certain human cancers. Here we show that preclinical models of synovial sarcoma - a cancer characterized by functional SMARCB1 loss via its displacement from the SWI/SNF complex through the pathognomonic SS18-SSX fusion protein - display sensitivity to pharmacologic inhibition of EZH2, the catalytic subunit of PRC2. Treatment with tazemetostat, a clinical-stage, selective and orally bioavailable small-molecule inhibitor of EZH2 enzymatic activity reverses a subset of synovial sarcoma gene expression and results in concentration-dependent cell growth inhibition and cell death specifically in SS18-SSX fusion-positive cells in vitro. Treatment of mice bearing either a cell line or two patient-derived xenograft models of synovial sarcoma leads to dose-dependent tumor growth inhibition with correlative inhibition of trimethylation levels of the EZH2-specific substrate, lysine 27 on histone H3. These data demonstrate a dependency of SS18-SSX-positive, SMARCB1-deficient synovial sarcomas on EZH2 enzymatic activity and suggests the potential utility of EZH2-targeted drugs in these genetically defined cancers.

2016-06-18 | GSE83479 | GEO

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2011-08-30 | GSE31715 | GEO

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