Omics · study · 2026
MDM2 degradation overcomes feedback regulation of p53 signaling in Merkel cell carcinoma
Listed in NCBI GEO
This study explored the efficacy of MDM2 degraders, KTX-049 and KT-253, in treating Merkel cell carcinoma (MCC), an aggressive skin cancer.
Description
MCC tumors often exhibit clonal integration of Merkel cell polyomavirus, with virus-positive (MCCP) and virus-negative (MCCN) tumors showing distinct molecular profiles. MDM2, a target of the ST-MYCL- Tip60 complex in MCCP, inhibits p53-mediated tumor suppression.
Our results demonstrate that KTX-049 is over 100 times more potent than the MDM2 inhibitor DS- 3032 in MCC cell lines with wild-type p53, effectively degrading MDM2 and activating the p53 response. Mathematical modeling indicates that KTX-049 collapses the p53-MDM2 feedback loop, enhancing its potency. In vivo, KT-253 induced robust and durable p53 pathway activation, producing deep tumor regressions in patient-derived xenograft models.
Read the rest (1 more)
However, the observed resistance was linked to TP53 mutations. These findings highlight the potential of MDM2 degraders as a therapeutic strategy for MCC and other tumor types with wild-type p53 and underscore the need for further investigation of resistance mechanisms and combination therapies.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE292nnn/GSE292992 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE292992 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1242314 ncbi.nlm.nih.gov/bioproject/PRJNA1242314 ↗
project · from NCBI GEO
- PubMed 42383359 pubmed.ncbi.nlm.nih.gov/42383359 ↗
publication · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Homo sapiens
- From keywords
- Life Sciences
- Inferred from text
- Cancer 75%
Provenance · 1 source records, 8 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE292992 | 15 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[disease].local:disease:cancer | 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[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 |