{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T19:11:20Z","timestamp":1782846680458,"version":"3.54.5"},"reference-count":51,"publisher":"American Society for Clinical Investigation","issue":"13","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"US Public Health Service","award":["R35CA232128"],"award-info":[{"award-number":["R35CA232128"]}]},{"name":"US Public Health Service","award":["P01CA203655"],"award-info":[{"award-number":["P01CA203655"]}]},{"name":"US Public Health Service","award":["R25CA174650"],"award-info":[{"award-number":["R25CA174650"]}]},{"name":"The Bridge Project, a partnership between the Koch Institute for Integrative Cancer Research at MIT and Harvard Cancer Consortium","award":["Traditional"],"award-info":[{"award-number":["Traditional"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,1]]},"abstract":"<jats:p>\n                    <jats:italic>MDM2<\/jats:italic>\n                    is transcriptionally activated by the ST-MYCL-Tip60 complex in virus-positive Merkel cell carcinoma (MCC). MDM2 suppresses p53 and is a rational therapeutic target. MDM2 inhibitors face an intrinsic limitation: p53 activation induces MDM2 transcription, creating a feedback loop that blunts inhibitor efficacy. We demonstrate that MDM2 degraders KTX-049 and KT-253 overcome this limitation by collapsing the p53\/MDM2 negative feedback loop. KTX-049 was &gt;100-fold more potent than the MDM2 inhibitor DS-3032 across WT p53 MCC cell lines, and this superior potency was quantitatively supported by mechanistic mathematical modeling. In vivo, KT-253 produced deep and durable tumor regressions, including complete responses in patient-derived xenograft models. Acquired resistance was strongly associated with acquisition of\n                    <jats:italic>TP53<\/jats:italic>\n                    mutations, confirming on-target pathway pressure. These findings establish feedback architecture as a critical determinant of therapeutic response and position MDM2 degradation as a qualitatively distinct strategy that produces more durable pathway engagement than MDM2 inhibition, providing a preclinical rationale for prioritizing MDM2 degraders in WT\n                    <jats:italic>TP53<\/jats:italic>\n                    MCC.\n                  <\/jats:p>","DOI":"10.1172\/jci199049","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T18:30:13Z","timestamp":1782844213000},"source":"Crossref","is-referenced-by-count":0,"title":["Targeted degradation of MDM2 overcomes feedback regulation of p53 signaling in Merkel cell carcinoma models"],"prefix":"10.1172","volume":"136","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6909-1460","authenticated-orcid":true,"given":"Varsha","family":"Ananthapadmanabhan","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA."},{"name":"Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Bruno","sequence":"additional","affiliation":[{"name":"Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USA."},{"name":"Department of Biostatistics, Harvard T.H. 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