GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE292nnn/GSE292992/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE292992GEOGSEfalseMDM2 degradation overcomes feedback regulation of p53 signaling in Merkel cell carcinomaThis 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.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 sapiens