ArticleCell2018
Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer.
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Article in Cell, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 142 papers.
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142citing papers in PubMed
9.7field-weighted citation impact, top 1% of its field
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Who cites it
142 citing papers in PubMed, 224 citations in OpenAlex.
- Phase I/II sequencing study of azacitidine, epacadostat, and pembrolizumab in advanced solid tumors.British journal of cancer · 2023Trial
- CDK7, CDK9, or CDK11 inhibition reduces neutrophil-driven inflammation and tissue damage in experimental autoimmune models.Cell communication and signaling : CCS · 2026Article
- Cyclins and Cyclin-Dependent Kinases: Structure, Biological Functions, and Innovative Targeting Strategies in Cancer.MedComm · 2026Review
- Targeting CDKs in the RNAPII transcription cycle.Nature reviews. Drug discovery · 2026Review
- Transposable Element Activation: A Hallmark of Cancer.Cancer discovery · 2026Review
- CDK9 inhibition sensitizes intrinsically resistantActa pharmaceutica Sinica. B · 2026Article
- Ribonucleotide Reductase Inhibition Overcomes FLT3 Inhibitor Resistance in Acute Myeloid Leukemia.bioRxiv : the preprint server for biology · 2026Article
- Next-generation sequencing elucidates the distinct mutational landscape of SMARCA4-deficient lung cancer.Oncology letters · 2026Article
- Drug Screening of Sarcoma Cells: Finding Shared Sensitivities.Cancer research communications · 2026Article
- CDK9 and hematologic malignancies: pioneering novel therapeutic approaches.Clinical and experimental medicine · 2026Review
- H3 dopaminylation and CaMKII modulate diffuse midline glioma response to CDK9 inhibition.bioRxiv : the preprint server for biology · 2026Article
- CDK2 inhibition promotes neuronal differentiation in neuroblastoma.Scientific reports · 2026Article
- ZMYM3 S464: a potential phospho-regulatory hub in epigenetic remodeling and oncogenesis.Molecular genetics and genomics : MGG · 2026Article
- MYC at the tumor-immune interface: mechanisms of immune escape and immunotherapy resistance.Frontiers in immunology · 2026Review
- CDK9 is a dependency in GATA-3 driven and MCL-1 independent T-cell Lymphomas.Blood cancer journal · 2025Article
- CDK8 mediated inflammatory microenvironment aggravates osteoarthritis progression.Journal of advanced research · 2025Article
- Dual Modes of Gene Regulation by CDK12.bioRxiv : the preprint server for biology · 2025Article
- Exploiting targeted degradation of cyclins and cyclin-dependent kinases for cancer therapeutics: a review.Journal of Zhejiang University. Science. B · 2025Review
- The role of E3 ligases and deubiquitinases in PD-L1 regulation and the tumor microenvironment in renal cell carcinoma.Medical oncology (Northwood, London, England) · 2025Review
- Targeting CDKs in cancer therapy: advances in PROTACs and molecular glues.NPJ precision oncology · 2025Review
82 more citing papers are in PubMed but not listed here.
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Authors and funding
33 authors at 7 institutions in 2 countries.
Hanghang ZhangFels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
Somnath PandeyFels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
Meghan TraversThe Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
Hongxing SunFels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
George MortonMoulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
Jozef MadzoFels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
Woonbok ChungFels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
Jittasak KhowsathitMolecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA.
Oscar Perez-LealDepartment of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
Carlos A BarreroDepartment of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
Carmen MeraliDepartment of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
Yasuyuki OkamotoFels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
Takahiro SatoFels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
Joshua PanDepartment of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
Judit GarrigaFels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
Natarajan V BhanuEpigenetics Institute, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Johayra SimithyEpigenetics Institute, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Bela PatelFels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
Jian HuangFels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
Noël J-M RaynalDépartement de pharmacologie et physiologie, Université de Montréal, Montréal, QC H3C 3J7, Canada.
Benjamin A GarciaEpigenetics Institute, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Marlene A JacobsonMoulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
Cigall KadochDepartment of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
Salim MeraliDepartment of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
Yi ZhangFels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
Wayne ChildersMoulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
Magid Abou-GharbiaMoulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
John KaranicolasMolecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Stephen B BaylinThe Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
Cynthia A ZahnowThe Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
Jaroslav JelinekFels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
Xavier GrañaFels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
Jean-Pierre J IssaFels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA. Electronic address: jpissa@temple.edu.
Temple University · USSidney Kimmel Comprehensive Cancer Center · USUniversity of Pennsylvania · USHarvard University · USFox Chase Cancer Center · USUniversité de Montréal · CAUniversity of Kansas · US
Funding
University of Texas M.D. Anderson Cancer SPORE-LeukemiaP50CA100632 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI KONOPLEVA, MARINA Y · 2003 to 2023
$43.7MShared Resources Core 2: Quantitative Proteomics CoreP01CA196539 · NCI · ROCKEFELLER UNIVERSITY · PI MUIR, TOM · 2015 to 2024
$17.6MViral modulation of epitranscriptomic mechanismsR01AI118891 · NIAID · WASHINGTON UNIVERSITY · PI GARCIA, BENJAMIN A, WEITZMAN, MATTHEW D. · 2015 to 2025
$5.4MRole of the microbiota in DNA methylation and CRC developmentR01CA214005 · NCI · TEMPLE UNIV OF THE COMMONWEALTH · PI ISSA, JEAN-PIERRE J., JOBIN, CHRISTIAN · 2018 to 2022
$2.9MDOT1L, reconstitution of plasmacytoid dendritic cells and alloimmunityR01HL154757 · NHLBI · TEMPLE UNIV OF THE COMMONWEALTH · PI ZHANG, YI · 2021 to 2024
$2.6MEzh2-mediated Epigenetic Effects and AlloimmunityR01HL127351 · NHLBI · TEMPLE UNIV OF THE COMMONWEALTH · PI ZHANG, YI · 2016 to 2019
$2.4MDelta-like ligand 4+ dendritic cells and induction of alloimmunityR01CA172106 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI ZHANG, YI · 2013 to 2017
$1.6MRegulators of Cancer-Specific DNA Hypermethylation.R01CA158112 · NCI · TEMPLE UNIV OF THE COMMONWEALTH · PI ISSA, JEAN-PIERRE J. · 2012 to 2016
$1.6MRobust Rational Design of Chemical Tools to Inhibit RNA-binding ProteinsR01GM123336 · NIGMS · RESEARCH INST OF FOX CHASE CAN CTR · PI KARANICOLAS, JOHN · 2017 to 2020
$1.5MUnraveling the complexity of substrate specificity of PP2A/B55a, a major eukaryote Serine/Threonine PhosphataseR01GM117437 · NIGMS · TEMPLE UNIV OF THE COMMONWEALTH · PI GRANA, XAVIER · 2016 to 2019
$1.3MUnderstanding the Role of Combinatorial Histone PTM PatternsR01GM110174 · NIGMS · UNIVERSITY OF PENNSYLVANIA · PI GARCIA, BENJAMIN A · 2014 to 2017
$1.3MTurning on Nrf2 translation for chronic liver diseaseR03DK105267 · NIDDK · TEMPLE UNIV OF THE COMMONWEALTH · PI PEREZ, OSCAR · 2015 to 2017
$552kNCI NIH HHS P01 CA196539NCI NIH HHS P50 CA100632NCI NIH HHS R01 CA158112NCI NIH HHS R01 CA172106NCI NIH HHS R01 CA214005NCI NIH HHS R03 CA216134NHLBI NIH HHS R01 HL127351NHLBI NIH HHS R01 HL154757NIAID NIH HHS R01 AI118891NIDDK NIH HHS R03 DK105267NIGMS NIH HHS R01 GM110174NIGMS NIH HHS R01 GM117437NIGMS NIH HHS R01 GM123336
Abstract
Cyclin-dependent kinase 9 (CDK9) promotes transcriptional elongation through RNAPII pause release. We now report that CDK9 is also essential for maintaining gene silencing at heterochromatic loci. Through a live cell drug screen with genetic confirmation, we discovered that CDK9 inhibition reactivates epigenetically silenced genes in cancer, leading to restored tumor suppressor gene expression, cell differentiation, and activation of endogenous retrovirus genes. CDK9 inhibition dephosphorylates the SWI/SNF protein BRG1, which contributes to gene reactivation. By optimization through gene expression, we developed a highly selective CDK9 inhibitor (MC180295, IC50 = 5 nM) that has broad anti-cancer activity in vitro and is effective in in vivo cancer models. Additionally, CDK9 inhibition sensitizes to the immune checkpoint inhibitor α-PD-1 in vivo, making it an excellent target for epigenetic therapy of cancer.
Indexed as
AnimalsCell Line, TumorCyclin-Dependent Kinase 9DNA HelicasesDNA MethylationFemaleGene Expression Regulation, NeoplasticHumansLeukocytes, MononuclearMaleMiceMice, Inbred C57BLMice, Inbred NODNuclear ProteinsProtein Kinase InhibitorsProto-Oncogene Proteins c-mycCyclin-Dependent Kinase 9DNA HelicasesNuclear ProteinsProtein Kinase InhibitorsProto-Oncogene Proteins c-mycRNA, Small InterferingSmall Molecule LibrariesSMARCA4 protein, humanTranscription FactorsBRG1CDK9DNA methylationdrug developmentepigenetic therapygene silencingimmunosensitizationkinase inhibitorsSMARCA4SWI/SNF
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