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

ABSTRACT: This study explores 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 a p53 response. Mathematical modeling suggests that KTX-049 disrupts the p53-MDM2 feedback loop, enhancing its potency. In vivo, KT-253 showed significant tumor growth inhibition in patient-derived xenograft models. However, observed resistance was linked to TP53 mutations. These findings highlight the potential of MDM2 degraders as a therapeutic strategy for MCC tumors with wild-type p53 and underscore the need for further investigation into resistance mechanisms and combination therapies.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Merkel Cell Carcinoma

SUBMITTER: Kymera Proteomics  

LAB HEAD: Kirti Sharma

PROVIDER: PXD065666 | Pride | 2026-03-31

REPOSITORIES: Pride