PXD065666

PXD065666 is an original dataset announced via ProteomeXchange.

Title	Targeted degradation of MDM2 overcomes feedback regulation of p53 signaling in Merkel cell carcinoma models.
Description	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.
HostingRepository	PRIDE
AnnounceDate	2026-03-31
AnnouncementXML	Submission_2026-03-31_12:50:36.882.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Kymera Proteomics
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Astral

Revision	Datetime	Status	ChangeLog Entry
0	2025-07-01 14:14:12	ID requested
⏵ 1	2026-03-31 12:50:37	announced

Dataset with its publication pending

submitter keyword: None

Kirti Sharma
contact affiliation	Kymera Therapeutics, United States
contact email	ksharma@kymeratx.com
lab head
Kymera Proteomics
contact affiliation	Kymera Therapeutics
contact email	proteomics_user@kymeratx.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/03/PXD065666

PRIDE project URI

• PRIDE
  1. PXD065666
     1. Label: PRIDE project
     2. Name: Targeted degradation of MDM2 overcomes feedback regulation of p53 signaling in Merkel cell carcinoma models.