ArticleMolecular cancer2023
CDK9 inhibition induces epigenetic reprogramming revealing strategies to circumvent resistance in lymphoma.
Article in Molecular cancer, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 32 citations in OpenAlex.
- CDK10 loss primes tumor cells for transcriptional vulnerability and sensitizes to CDK12/13 inhibition.Cell death & disease · 2026Article
- CDK9 and hematologic malignancies: pioneering novel therapeutic approaches.Clinical and experimental medicine · 2026Review
- Cyclin-Dependent Kinase-9 and Oxidative Phosphorylation Inhibition Overcomes Ibrutinib Resistance in Mantle Cell Lymphoma.Cancer research communications · 2026Article
- Elastic enhancer network tunes equilibrium thermodynamics of liquid liquid phase separation in super enhancers.iScience · 2026Article
- Cardiomyocyte Cyclin-dependent kinase 9 directly binds to and phosphorylates NF-κB p65 subunit to drive cardiac inflammation and remodeling.Nature communications · 2026Article
- Crosstalk BetweenCancers · 2026Review
- Enitociclib (VIP152), venetoclax and prednisone in relapsed or refractory aggressive non-Hodgkin lymphoma.British journal of haematology · 2026Article
- Introduction to Cancer Metabolism.Cancer treatment and research · 2026Review
- The EP300-Targeting Drug CCS1477 Inhibits the Growth and Development of Diffuse Large B-Cell Lymphoma by Promoting Apoptosis and Mitophagy to Reduce Drug Resistance.Anti-cancer agents in medicinal chemistry · 2026Article
- Epigenetics and One-Carbon Metabolism in Cancer: Mechanisms and Therapeutic Implications.Advances in experimental medicine and biology · 2026Review
- Targeting CDK9-dependent transcriptional addiction: a novel chemoprevention strategy for oral carcinogenesis via adenosine deaminase modulation.Cell death & disease · 2025Article
- ALKBH1 Drives Tumorigenesis and Drug Resistance via tRNA-decoding Reprogramming and Codon-biased Translation.Cancer discovery · 2025Article
- Single-Cell Analysis of L-Myc Expressing Neural Stem Cells and Their Extracellular Vesicles Revealed Distinct Progenitor Populations With Neurogenic Potential.Journal of extracellular biology · 2025Article
- Enhancer regulation in cancer: from epigenetics to mArchives of pharmacal research · 2025Review
- STAT3 Facilitates Super Enhancer Formation to Promote Fibroblast-To-Myofibroblast Differentiation by the Analysis of ATAC-Seq, RNA-Seq and ChIP-Seq.Journal of cellular and molecular medicine · 2025Review
- MYC networks associate with decreased CD8 T-cell presence in diffuse large B-cell lymphoma and may be addressed by the synergistic combination of AZD4573 and Selinexor - a preliminary analysis.Annals of hematology · 2025Article
- A phase 1 study of the CDK9 inhibitor voruciclib in relapsed/refractory acute myeloid leukemia and B-cell malignancies.Blood advances · 2025Article
- Super-enhancers in tumors: unraveling recent advances in their role in Oncogenesis and the emergence of targeted therapies.Journal of translational medicine · 2025Review
- Targeting protein synthesis pathways in MYC-amplified medulloblastoma.Discover oncology · 2025Review
- Super-enhancers in hepatocellular carcinoma: regulatory mechanism and therapeutic targets.Cancer cell international · 2025Review
Corrections and comments
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Authors and funding
14 authors at 4 institutions in 2 countries.
Funding
Abstract
Diffuse large B-cell lymphoma (DLBCL) exhibits significant genetic heterogeneity which contributes to drug resistance, necessitating development of novel therapeutic approaches. Pharmacological inhibitors of cyclin-dependent kinases (CDK) demonstrated pre-clinical activity in DLBCL, however many stalled in clinical development. Here we show that AZD4573, a selective inhibitor of CDK9, restricted growth of DLBCL cells. CDK9 inhibition (CDK9i) resulted in rapid changes in the transcriptome and proteome, with downmodulation of multiple oncoproteins (eg, MYC, Mcl-1, JunB, PIM3) and deregulation of phosphoinotiside-3 kinase (PI3K) and senescence pathways. Following initial transcriptional repression due to RNAPII pausing, we observed transcriptional recovery of several oncogenes, including MYC and PIM3. ATAC-Seq and ChIP-Seq experiments revealed that CDK9i induced epigenetic remodeling with bi-directional changes in chromatin accessibility, suppressed promoter activation and led to sustained reprograming of the super-enhancer landscape. A CRISPR library screen suggested that SE-associated genes in the Mediator complex, as well as AKT1, confer resistance to CDK9i. Consistent with this, sgRNA-mediated knockout of MED12 sensitized cells to CDK9i. Informed by our mechanistic findings, we combined AZD4573 with either PIM kinase or PI3K inhibitors. Both combinations decreased proliferation and induced apoptosis in DLBCL and primary lymphoma cells in vitro as well as resulted in delayed tumor progression and extended survival of mice xenografted with DLBCL in vivo. Thus, CDK9i induces reprogramming of the epigenetic landscape, and super-enhancer driven recovery of select oncogenes may contribute to resistance to CDK9i. PIM and PI3K represent potential targets to circumvent resistance to CDK9i in the heterogeneous landscape of DLBCL.
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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.