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Single-cell RNA-seq analysis of immune microenvironment changes in pancreatic cancer following combined EZH2 and KRAS inhibition

ABSTRACT: Our study demonstrated that combined treatment with the EZH2 inhibitor tazemetostat and the KRAS inhibitor RMC-6236 significantly suppressed the growth of both subcutaneous and orthotopic tumors. To investigate changes in the tumor microenvironment following combined EZH2 and KRAS inhibition in pancreatic cancer, mice bearing subcutaneous KPC tumors were treated with vehicle, RMC-6236 alone, or RMC-6236 in combination with tazemetostat. CD45⁺ cells were isolated and subjected to 10× Genomics single-cell RNA sequencing.

ORGANISM(S): Mus musculus

PROVIDER: GSE315131 | GEO | 2026/01/31

REPOSITORIES: GEO

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Differential mRNA expression analysis of multiple human and mouse pancreatic cancer cells and tumors after DMSO, tazemetostat, RMC-6236, or the combination treatment.

Project description:Our study demonstrated that combined treatment with the EZH2 inhibitor tazemetostat and the KRAS inhibitor RMC-6236 significantly suppressed the growth of subcutaneous and orthotopic tumors. To investigates the transcriptional effects of combined EZH2 and KRAS inhibition in pancreatic cancer models, transcriptome profiling was performed in PSN1, SW1990, and KPC cells treated with DMSO, tazemetostat, RMC-6236, or the combination of both inhibitors. In parallel, orthotopic KPC tumors subjected to the same treatments were harvested for RNA sequencing. In addition, an acquired resistance model to RMC-6236 was established in mice, and tumors treated with RMC-6236 alone or in combination with tazemetostat were collected at different stages for RNA-seq analysis to characterize dynamic changes in gene expression profiles.

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ChIP-seq analysis of H3K27ac changes in pancreatic cancer cells treated with EZH2 and KRAS inhibitors

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2024-03-15 | PXD047878 | Pride

RAS(ON) multi-selective inhibition drives anti-tumor immunity in preclinical models of NRAS-mutant melanoma

Project description:Targeted therapies for NRAS-mutant melanoma remain an unmet clinical need. Here, we demonstrate that RMC-7977, a preclinical RAS(ON) multi-selective inhibitor respresentative of the investigational agent daraxonrasib (RMC-6236), elicits potent anti-tumor immune responses across several NRAS-mutant melanoma models. Treatment with RMC-7977 led to rapid tumor regressions driven by inhibition of MAPK signaling, upregulation of MHC and PD-L1 proteins, and enhanced infiltration of CD4⁺ and CD8⁺ T cells. Complete responses was dependent on adaptive immunity, as both CD4⁺ and CD8⁺ T cells were essential for extended survival. Resistance to treatment was marked by reduced T cell infiltration, loss of MHCI expression, and expansion of MDSCs. Combining RMC-7977 with anti-PD-1 boosted T cytotoxic cell infiltration, reprogrammed myeloid cells toward an antigen-presenting phenotype, and improved survival in models resistant to PD-1 blockade. Notably, objective clinical responses were observed in two NRAS-mutant melanoma patients treated with daraxonrasib (RMC-6236) in an ongoing phase I/Ib clinical trial.

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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.

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Differential mRNA expression analysis of multiple human and mouse pancreatic cancer cells and tumors after DMSO, tazemetostat, RMC-6236, or the combination treatment.

Project description:Differential mRNA expression analysis of multiple human and mouse pancreatic cancer cells and tumors after DMSO, tazemetostat, RMC-6236, or the combination treatment.

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RNAseq of human cell line RPCI-WM1 comparing artificial PRDM1-targeting miRNA to non-targeting control, and comparing Tazemetostat treatment to DMSO. ChIPseq for the factors BLIMP1 and H3K27me3 in the RPCI-WM1, OPM-2 and NCI-H929 cell lines, along with ChIPseq for EZH2 in the NCI-H929 cell line.

Project description:To identify the role of BLIMP1 in Waldenström's macroglobulinemia, the PRDM1 transcript was targeted using an artificial miRNA. RNAseq was used to compare it to a non-targeting control in the RPCI-WM1 cell line. To determine the role of EZH2 in Waldenström's macroglobulinemia, the RPCI-WM1 cell line was treated with 0.3µM of the EZH2 inhibitor Tazemetostat, compared to DMSO vehicle control by RNAseq. ChIPseq was performed for the factors BLIMP1 and H3K27me3 in the RPCI-WM1, OPM-2 and NCI-H929 cell lines, along with ChIPseq for EZH2 in the NCI-H929 cell line.

2019-05-07 | E-MTAB-7739 | biostudies-arrayexpress

EZH2 inhibition in mesothelioma cells increases the release of extracellular vesicles that skew neutrophils toward a pro-tumor phenotype.

Project description:BAP1-deficient pleural mesotheliomas have been shown to be sensitive to inhibition of the histone methyltransferase EZH2 in preclinical settings but only showed modest efficacy in clinical trials. We recently demonstrated that in BAP1-proficient mesothelioma cells, CDKN2A plays a crucial role in response to the selective EZH2 inhibitor tazemetostat. Therefore, in the current study, we employed a quantitative proteomic mass spectrometry approach to analyze changes in protein expression in response to tazemetostat in BAP1-CDKN2A proficient MSTO-211H cells cultured as spheroids. Our results demonstrate that tazemetostat treatment induced an increase in the expression of 21 proteins and a decrease in the expression of 12 proteins. Notably, RAB27b and CD63 were among the most up-regulated proteins. We also demonstrate that higher levels of RAB27b and CD63 were linked to a heightened release of extracellular vesicles (EVs). When exploring the impact of tumor-derived EVs on naïve neutrophil behavior, we found that brief exposure to EVs derived from tazemetostat-treated cells skewed naïve neutrophils toward a pro-tumor phenotype characterized by high levels of PD-L1 and mesothelin surface expression. These EV-elicited neutrophils suppressed lymphocyte proliferation while enhancing tumor cell growth. Interestingly, most up-regulated proteins in EV cargo derived from tazemetostat-treated spheroids were FZD6, the catalytic subunit alpha of PI3K and PPAR-α, while the most downregulated was ENOX2.

2025-11-24 | PXD057566 | Pride

The EZH2 inhibitor tazemetostat mitigates HIV immune evasion, reduces reservoir formation, and promotes durable CD8⁺ T-cell revitalization

Project description:Persistent HIV reservoirs in CD4⁺ T-cells impede efforts to cure HIV infection. We identified overexpression of enhancer of zeste homolog 2 (EZH2) in HIV-infected CD4⁺ T-cells that survive cytotoxic T lymphocyte (CTL) exposure, suggesting a mechanism of CTL resistance. Inhibition of EZH2 with the FDA-approved drug tazemetostat increased surface expression of major histocompatibility complex class I (MHC-I) on CD4⁺ T-cells, counteracting HIV Nef–mediated MHC-I downregulation. This enhancement improved CTL-mediated elimination of HIV-infected cells and suppressed viral replication in vitro. In a participant-derived xenograft mouse model, tazemetostat elevated MHC-I and the pro-apoptotic protein BIM in CD4⁺ T-cells, facilitating CD8⁺ T-cell–mediated reduction of HIV reservoir seeding. Additionally, tazemetostat promoted sustained skewing of CD8⁺ T-cells toward less differentiated and less exhausted phenotypes. Our findings reveal EZH2 overexpression as a novel mechanism of CTL resistance and support the clinical evaluation of tazemetostat to enhance immune-mediated clearance of HIV reservoirs.

2026-01-26 | PXD061146 | Pride

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