ArticleBlood2018
Mechanisms of resistance to EZH2 inhibitors in diffuse large B-cell lymphomas.
Article in Blood, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 81 papers.
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Who cites it
81 citing papers in PubMed, 136 citations in OpenAlex.
- Proteolysis Targeting Chimeric-Based Technology in Myeloma and Lymphoma.Molecular cancer therapeutics · 2026Review
- Druggability assessments of small peptides as protein-protein interaction inhibitors targeting EED-EZH2 binding within the Polycomb Repressive Complex 2 (PRC2), an epigenetic regulator.Molecular diversity · 2026Article
- Repurposing acetyldigitoxin as a potential EZH2 inhibitor for non-small cell lung cancer: a computational and experimental approach.Journal of computer-aided molecular design · 2026Article
- Mechanisms of chemoresistance in diffuse large B‑cell lymphoma and novel therapeutic strategies (Review).International journal of oncology · 2026Review
- Structural landscape of H3K27me3 recognition by protein domains and their potential for inhibition.The Journal of biological chemistry · 2026Review
- Biological Evaluation of a Novel Compound with Predicted EZH2 and EED Binding Against Human Malignant Melanoma Cells.International journal of molecular sciences · 2026Article
- Exploring the role of EZH2 in neuroinflammation: implications for innovative therapeutic strategies.Naunyn-Schmiedeberg's archives of pharmacology · 2026Review
- EZH2 PROTACs outperform catalytic inhibitors in prostate cancer by targeting a methylation-independent function of PRC2.Oncogene · 2026Article
- Therapeutic horizons in the development of PROTAC-based EZH2 inhibitors: recent achievements, comparative analysis, and future perspectives.RSC advances · 2026Review
- Potential of small-molecule targeted drugs in combination with CAR-T cell therapy for hematologic lymphomas.Frontiers in immunology · 2026Review
- Exploring KAT6 as a therapeutic target in breast cancer: epigenetic approaches for precision medicine.NPJ breast cancer · 2025Review
- Epigenetic reprogramming drives endothelial dysfunction via neuropilin-1 in pulmonary hypertension.Molecular medicine (Cambridge, Mass.) · 2025Article
- Overcoming CAR-T bottlenecks in high-risk DLBCL: a molecular subtyping enhancement strategy.Cancer cell international · 2025Review
- Epigenetic reprogramming as the nexus of cancer stemness and therapy resistance: implications for biomarker discovery.Discover oncology · 2025Review
- Therapeutic Targeting of Protein Lysine and Arginine Methyltransferases: Principles and Strategies for Inhibitor Design.International journal of molecular sciences · 2025Review
- Interaction between stromal cells and tumor cells promotes GCB-DLBCL cell survival via the CD40/RANK-KDM6B-NF-κB axis.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Exploring oncogenic roles and clinical significance of EZH2: focus on non-canonical activities.Therapeutic advances in medical oncology · 2025Review
- Pharmacological Advancements of PRC2 in Cancer Therapy: A Narrative Review.Life (Basel, Switzerland) · 2024Review
- Targeting EZH2 in Cancer: Mechanisms, Pathways, and Therapeutic Potential.Molecules (Basel, Switzerland) · 2024Review
- Overcoming Clinical Resistance to EZH2 Inhibition Using Rational Epigenetic Combination Therapy.Cancer discovery · 2024Article
21 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Resistance to targeted therapies has become increasingly prevalent. We noted that resistance to different targeted therapies occurs by largely common mechanisms. In this study, we used this information for identifying the mechanisms of resistance to enhancer of zeste homolog 2 (EZH2) inhibitors in diffuse large B-cell lymphoma (DLBCL) harboring EZH2 mutations. We discovered that EZH2 inhibitor-resistant DLBCL cells showed activation of the insulin-like growth factor 1 receptor (IGF-1R), MEK, and phosphoinositide-3-kinase (PI3K) pathways. Constitutive activation of IGF-1R, MEK, or PI3K pathways was sufficient to confer resistance to EZH2 inhibitors in DLBCL. The activation of the PI3K/AKT and MAPK pathways decreased TNFSF10 and BAD expression through a FOXO3-dependent mechanism, which was required for the antitumor effects of EZH2i GSK126. We also identified multiple acquired mutations in EZH2 inhibitor-resistant DLBCL cell lines. These mutations independently conferred resistance to EZH2 inhibitors. Mechanistically, cellular thermal shift assays revealed that the acquired EZH2 mutations that confer resistance to EZH2 inhibitors prevent EZH2 inhibitor binding to the EZH2 mutants. Notably, EZH2 inhibitor GSK126- and EPZ-6438-resistant DLBCL cells remained sensitive to the EZH2 inhibitor UNC1999 and embryonic ectoderm development protein inhibitor EED226, which provides an opportunity to treat DLBCLs that are resistant to these drugs. Collectively, our results underpin the importance for developing a unified approach for forestalling drug resistance by prospectively considering lessons learned from the use of different targeted therapeutic agents.
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Registered trials
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.