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Overcoming clinical resistance to EZH2 inhibition using rational epigenetic combination therapy

ABSTRACT: Overcoming clinical resistance to EZH2 inhibition using rational epigenetic combination therapy

PROVIDER: PRJNA928834 | ENA |

REPOSITORIES: ENA

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Overcoming clinical resistance to EZH2 inhibition using rational epigenetic combination therapy

Project description:Overcoming clinical resistance to EZH2 inhibition using rational epigenetic combination therapy

| PRJNA928835 | ENA

Overcoming clinical resistance to EZH2 inhibition using rational epigenetic combination therapy

Project description:Overcoming clinical resistance to EZH2 inhibition using rational epigenetic combination therapy

| PRJNA882766 | ENA

Overcoming clinical resistance to EZH2 inhibition using rational epigenetic combination therapy

Project description: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.

2023-02-07 | GSE213845 | GEO

YM155 in combination with EZH2 inhibiton induces synthetic lethality

Project description:YM155 in combination with EZH2 inhibiton induces synthetic lethality

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Combination of EZH2 inhibitor and STING agonist in melanoma cell lines

Project description:In order to better understand the effects of combination treatment with EZH2 inhibitor and STING agonist in human melanoma cells, RNA sequencing was performed to explore transcriptome alteration.

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Bioinformatics-driven discovery of rational combination for overcoming EGFR-mutant lung cancer resistance to EGFR therapy.

Project description:Non-small-cell lung cancer (NSCLC) is the leading cause of cancer death in the United States. Targeted tyrosine kinase inhibitors (TKIs) directed against the epidermal growth factor receptor (EGFR) have been widely and successfully used in treating NSCLC patients with activating EGFR mutations. Unfortunately, the duration of response is short-lived, and all patients eventually relapse by acquiring resistance mechanisms.We performed an integrative systems biology approach to determine essential kinases that drive EGFR-TKI resistance in cancer cell lines. We used a series of bioinformatics methods to analyze and integrate the functional genetics screen and RNA-seq data to identify a set of kinases that are critical in survival and proliferation in these TKI-resistant lines. By connecting the essential kinases to compounds using a novel kinase connectivity map (K-Map), we identified and validated bosutinib as an effective compound that could inhibit proliferation and induce apoptosis in TKI-resistant lines. A rational combination of bosutinib and gefitinib showed additive and synergistic effects in cancer cell lines resistant to EGFR TKI alone.We have demonstrated a bioinformatics-driven discovery roadmap for drug repurposing and development in overcoming resistance in EGFR-mutant NSCLC, which could be generalized to other cancer types in the era of personalized medicine.K-Map can be accessible at: http://tanlab.ucdenver.edu/kMap.Supplementary data are available at Bioinformatics online.

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Affinify Purification of EZH2 and phosphodeficient EZH2 identifies phosphorylation dependent interactions of EZH2

Project description:Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. We have shown that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. Here, we explore the interactome of EZH2 and of a phosphodeficient mutant EZH2_T367A. We identified novel interactors of EZH2, and identified interactions that are dependent on the phosphorylation and cellular localization of EZH2 that may play a role in EZH2 dependent metastatic progression.

2018-07-03 | PXD010073 | Pride

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Project description:Combination of EZH2 inhibitor and STING agonist in melanoma cell lines

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Combined inhibition of histone methyltransferases EZH2 and DOT1L is an effective therapy for neuroblastoma

Project description:The child cancer, neuroblastoma (NB), is characterised by a low incidence of mutations and strong oncogenic embryonal driver signals. Many new targeted epigenetic modifier drugs have failed in human trials as monotherapy. We performed a high‐throughput, combination chromatin‐modifier drug screen against NB cells. We screened 13 drug candidates in 78 unique combinations. We found that the combination of two histone methyltransferase (HMT) inhibitors: GSK343, targeting EZH2, and SGC0946, targeting DOT1L, demonstrated the strongest synergy across 8 NB cell lines, with low normal fibroblast toxicity. High mRNA expression of both EZH2 and DOT1L in NB tumour samples correlated with the poorest patient survival. Combination HMT inhibitor treatment caused activation of ATF4‐mediated endoplasmic reticulum (ER) stress responses. In addition, glutathione and several amino acids were depleted by HMT inhibitor combination on mass spectrometry analysis. The combination of SGC0946 and GSK343 reduced tumour growth in comparison to single agents. Our results support further investigation of HMT inhibitor combinations as a therapeutic approach in NB.

2024-11-13 | GSE281811 | GEO

YM155 in combination with EZH2 inhibiton induces synthetic lethality

Project description:EZH2 inhibitors have been developed to treat certain cancers. To maximize the anticancer acttivity of EZH2 inhibition, we combined an EZH2 inhibitor EPZ6438 with YM155, which leads to dramatic cell death. We used microarrays to detail the global gene expression profiles.

2023-01-13 | GSE208593 | GEO

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