Omics · study · 2026
CDK12 as an entry point for combination therapy in high-risk neuroblastoma [RNA-seq]
Listed in NCBI GEO
High-risk neuroblastoma (HR-NB) patients undergo aggressive treatments, yet more than half succumb to the disease.
Description
HR-NB cells are marked by chronic replicative stress, partly driven by MYCN amplification, and targeting DNA damage response (DDR) pathways presents a promising therapeutic approach. BRCA1 and CDK12, located on the recurrently gained 17q region in HR-NB, play essential roles in maintaining genomic stability.
In this study, we hypothesized that pharmacological inactivation of CDK12 could induce a BRCAness phenotype, making NB cells vulnerable to synthetic lethal targets. We evaluated the efficacy of CDK12 inhibitors and protein degraders in a panel of NB cell lines and organoids. Molecular effects of CDK12 inactivation were investigated through immunoblotting and RNA-sequencing.
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A high-throughput compound screen combining CDK12-targeting agents with a library of ~200 drugs revealed that single-agent treatment with CDK12 inhibitors or degraders induced significant NB cell death in vitro. This was accompanied by a BRCAness signature, including decreased BRCA1 and RAD51 levels, increased DNA damage, and downregulation of DNA repair genes. Additionally, we observed upregulation of immune pathways, suggesting potential for enhancing immunogenicity in HR-NB.
The combinatorial drug screen revealed strong synergy with DNA-damaging agents, PARP inhibitors, Ras/MAPK inhibitors, and other compounds. These findings confirm CDK12 as a novel therapeutic target, and the induction of a BRCAness phenotype provides a basis for combination treatments.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE287nnn/GSE287496 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE287496 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1213098 ncbi.nlm.nih.gov/bioproject/PRJNA1213098 ↗
project · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Homo sapiens
- From keywords
- Life Sciences
- Inferred from text
- Disease 75% · RNA sequencing 65%
Provenance · 1 source records, 9 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE287496 | 14 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[disease].local:disease:disease | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[modality].local:modality:rna-seq | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (65%) |
| concepts[organism].NCBITaxon:9606 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |