MDM2 degradation overcomes feedback regulation of p53 signaling in Merkel cell carcinoma

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.