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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

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			Action	DRS
	2403LH0372_N9_MCC328Veh1_20240328173233.raw	Raw
	2403LH0372_N9_MCC328Veh2_20240328182535.raw	Raw
	2403LH0372_N9_MCC328Veh3_20240328191831.raw	Raw
	2403LH0372_N9_MCC328Veh4_20240328201127.raw	Raw
	2403LH0372_N9_MCC335Veh1_20240328210423.raw	Raw

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Project description:Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine tumor with high mortality rates. Merkel cell polyomavirus (MCPyV), identified in the majority of MCC, may drive tumorigenesis via viral T antigens. However, mechanisms underlying pathogenesis in MCPyV-negative MCC remain poorly understood. To nominate genes contributing to pathogenesis of MCPyV-negative MCC, we performed DNA microarray analysis on 30 MCCs. MCPyV status of MCCs was determined by PCR for viral DNA and RNA. 1593 probe-sets were differentially expressed between MCPyV-negative and -positive MCC, with significant differential expression defined as at least 2-fold change in either direction and p-value of ≤ 0.05. MCPyV-negative tumors showed decreased RB1 expression, whereas MCPyV-positive tumors were enriched for immune response genes. Validation studies included immunohistochemistry demonstration of decreased RB protein expression in MCPyV-negative tumors and increased peritumoral CD8+ T lymphocytes surrounding MCPyV-positive tumors. In conclusion, our data suggest that loss of RB1 expression may play an important role in tumorigenesis of MCPyV-negative MCC. Functional and clinical validation studies are needed to determine whether this tumor suppressor pathway represents an avenue for targeted therapy. We used microarrays to characterize global gene expression patterns related to Merkel cell polyomavirus status in Merkel cell carcinoma. Furthermore, we compared Merkel cell carcinoma to less aggressive primary cutaneous carcinomas. We utilized flash-frozen tumor tissue from primary Merkel cell carcinomas, metastatic Merkel cell carcinomas, primary cutaneous squamous cell carcinomas, and basal cell carcinomas. Merkel cell carcinoma cell lines, which represent a pure population of tumor cells, were also included. Merkel cell polyomavirus status was determined at the DNA and RNA level using multiple primers for viral T-antigen and capsid protein sequences. This Series represents two analyses - one with new Samples normalized together, and another with some of the new Samples re-normalized with Samples previously submitted under Series GSE13355. The latter group contain 'renormalized' in the titles.

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

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