{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE292nnn/GSE292992/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE292992"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"MDM2 degradation overcomes feedback regulation of p53 signaling in Merkel cell carcinoma","description":"This study explored the efficacy of MDM2 degraders, KTX-049 and KT-253, in treating Merkel cell carcinoma (MCC), an aggressive skin cancer. 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. 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.","dates":{"publication":"2026/04/02"},"accession":"GSE292992","cross_references":{"GSM":["GSM8872791","GSM8872790","GSM8872751","GSM8872795","GSM8872750","GSM8872794","GSM8872793","GSM8872792","GSM8872799","GSM8872755","GSM8872754","GSM8872798","GSM8872796","GSM8872752","GSM8872759","GSM8872758","GSM8872757","GSM8872756","GSM8872749","GSM8872762","GSM8872761","GSM8872760","GSM8872766","GSM8872765","GSM8872763","GSM8872803","GSM8872802","GSM8872769","GSM8872768","GSM8872801","GSM8872767","GSM8872800","GSM8872773","GSM8872772","GSM8872771","GSM8872770","GSM8872733","GSM8872777","GSM8872776","GSM8872774","GSM8872737","GSM8872736","GSM8872779","GSM8872735","GSM8872734","GSM8872778","GSM8872804","GSM8872780","GSM8872784","GSM8872740","GSM8872783","GSM8872782","GSM8872781","GSM8872744","GSM8872788","GSM8872742","GSM8872786","GSM8872741","GSM8872785","GSM8872748","GSM8872747","GSM8872746","GSM8872745","GSM8872789","GSM8872739","GSM8872738"],"GPL":["34284"],"GSE":["292992"],"taxon":["Homo sapiens"]}}