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The novel RNA polymerase I transcription inhibitor PMR-116 exploits a critical therapeutic vulnerability in a broad-spectrum of high MYC malignancies [ChIP-Seq]

ABSTRACT: Ribosome biogenesis (RiBi) is a key determinant of cell growth and proliferation and is highly elevated in cancer due to the activation by oncogenes such as MYC. First-generation RiBi inhibitor CX-5461, while demonstrating clinical potential for cancer treatment, also induces DNA damage through off-target inhibition of TOP2⍺ and potentially other mechanisms, bringing into question RiBi as a target for cancer therapy. In this study, we test second-generation RiBi inhibitor, PMR-116. PMR-116 exhibits improved drug-like properties compared to first-generation RiBi inhibitors and has robust anti-tumour activity in the absence of global DNA damage signalling in a broad range of pre-clinical models of haematologic and solid cancers, particularly in malignancies where MYC is either the driver of disease or is elevated. Thus, our work demonstrates that RiBi is a genuine target for cancer therapy and highlights the potential to exploit a critical therapeutic vulnerability in high-MYC human cancers with dismal therapeutic outcomes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE302076 | GEO | 2025/07/08

REPOSITORIES: GEO

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Project description:modENCODE_submission_3598 This submission comes from a modENCODE project of Michael Snyder. For full list of modENCODE projects, see http://www.genome.gov/26524648 Project Goal: We are identifying the DNA binding sites for 300 transcription factors in C. elegans. Each transcription factor gene is tagged with the same GFP fusion protein, permitting validation of the gene's correct spatio-temporal expression pattern in transgenic animals. Chromatin immunoprecipitation on each strain is peformed using an anti-GFP antibody, and any bound DNA is deep-sequenced using Solexa GA2 technology. For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf EXPERIMENT TYPE: CHIP-seq. BIOLOGICAL SOURCE: Strain: OP226(official name : OP226 genotype : unc119(ed3);wgIs226(nhr-116::TY1 EGFP FLAG;unc119) outcross : 3 transgene : nhr-116 tags : Bombard tag : GFP::3xFlag description : This strain's transgene was constructed by Mihail Sarov at the Max Planck Institute for Cell Biology in Tubiginen using Tony Hyman's recombineering pipeline. The resulting plasmid was used for biolistic transformation of an unc-119(ed3) strain. The NHR-116::EGFP fusion protein is expressed in the correct nhr-116 spatio-temporal expression pattern. This strain was used for ChIP-seq experiments to map the in vivo binding sites for the NHR-116 transcription factor. made_by : M Sarov ); Developmental Stage: L2; Genotype: unc119(ed3);wgIs226(nhr-116::TY1 EGFP FLAG;unc119); Sex: Hermaphrodite; Transgene: nhr-116; EXPERIMENTAL FACTORS: Developmental Stage L2; Target gene nhr-116; Strain OP226(official name : OP226 genotype : unc119(ed3);wgIs226(nhr-116::TY1 EGFP FLAG;unc119) outcross : 3 transgene : nhr-116 tags : Bombard tag : GFP::3xFlag description : This strain's transgene was constructed by Mihail Sarov at the Max Planck Institute for Cell Biology in Tubiginen using Tony Hyman's recombineering pipeline. The resulting plasmid was used for biolistic transformation of an unc-119(ed3) strain. The NHR-116::EGFP fusion protein is expressed in the correct nhr-116 spatio-temporal expression pattern. This strain was used for ChIP-seq experiments to map the in vivo binding sites for the NHR-116 transcription factor. made_by : M Sarov ); temp (temperature) 20 degree celsius

Project description:modENCODE_submission_3599 This submission comes from a modENCODE project of Michael Snyder. For full list of modENCODE projects, see http://www.genome.gov/26524648 Project Goal: We are identifying the DNA binding sites for 300 transcription factors in C. elegans. Each transcription factor gene is tagged with the same GFP fusion protein, permitting validation of the gene's correct spatio-temporal expression pattern in transgenic animals. Chromatin immunoprecipitation on each strain is peformed using an anti-GFP antibody, and any bound DNA is deep-sequenced using Solexa GA2 technology. For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf EXPERIMENT TYPE: CHIP-seq. BIOLOGICAL SOURCE: Strain: OP226(official name : OP226 genotype : unc119(ed3);wgIs226(nhr-116::TY1 EGFP FLAG;unc119) outcross : 3 transgene : nhr-116 tags : Bombard tag : GFP::3xFlag description : This strain's transgene was constructed by Mihail Sarov at the Max Planck Institute for Cell Biology in Tubiginen using Tony Hyman's recombineering pipeline. The resulting plasmid was used for biolistic transformation of an unc-119(ed3) strain. The NHR-116::EGFP fusion protein is expressed in the correct nhr-116 spatio-temporal expression pattern. This strain was used for ChIP-seq experiments to map the in vivo binding sites for the NHR-116 transcription factor. made_by : M Sarov ); Developmental Stage: L4; Genotype: unc119(ed3);wgIs226(nhr-116::TY1 EGFP FLAG;unc119); Sex: Hermaphrodite; Transgene: nhr-116; EXPERIMENTAL FACTORS: Developmental Stage L4; Target gene nhr-116; Strain OP226(official name : OP226 genotype : unc119(ed3);wgIs226(nhr-116::TY1 EGFP FLAG;unc119) outcross : 3 transgene : nhr-116 tags : Bombard tag : GFP::3xFlag description : This strain's transgene was constructed by Mihail Sarov at the Max Planck Institute for Cell Biology in Tubiginen using Tony Hyman's recombineering pipeline. The resulting plasmid was used for biolistic transformation of an unc-119(ed3) strain. The NHR-116::EGFP fusion protein is expressed in the correct nhr-116 spatio-temporal expression pattern. This strain was used for ChIP-seq experiments to map the in vivo binding sites for the NHR-116 transcription factor. made_by : M Sarov ); temp (temperature) 20 degree celsius

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The novel RNA polymerase I transcription inhibitor PMR-116 exploits a critical therapeutic vulnerability in a broad-spectrum of high MYC malignancies [ChIP-Seq]

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