{"doi":"10.1158/2159-8290.cd-22-1131","title":"Targeted MDM2 Degradation Reveals a New Vulnerability for p53-Inactivated Triple-Negative Breast Cancer","abstract":"Triple-negative breast cancers (TNBC) frequently inactivate p53, increasing their aggressiveness and therapy resistance. We identified an unexpected protein vulnerability in p53-inactivated TNBC and designed a new PROteolysis TArgeting Chimera (PROTAC) to target it. Our PROTAC selectively targets MDM2 for proteasome-mediated degradation with high-affinity binding and VHL recruitment. MDM2 loss in p53 mutant/deleted TNBC cells in two-dimensional/three-dimensional culture and TNBC patient explants, including relapsed tumors, causes apoptosis while sparing normal cells. Our MDM2-PROTAC is stable in vivo, and treatment of TNBC xenograft-bearing mice demonstrates tumor on-target efficacy with no toxicity to normal cells, significantly extending survival. Transcriptomic analyses revealed upregulation of p53 family target genes. Investigations showed activation and a required role for TAp73 to mediate MDM2-PROTAC-induced apoptosis. Our data, challenging the current MDM2/p53 paradigm, show MDM2 is required for p53-inactivated TNBC cell survival, and PROTAC-targeted MDM2 degradation is an innovative potential therapeutic strategy for TNBC and superior to existing MDM2 inhibitors. SIGNIFICANCE: p53-inactivated TNBC is an aggressive, therapy-resistant, and lethal breast cancer subtype. We designed a new compound targeting an unexpected vulnerability we identified in TNBC. Our MDM2-targeted degrader kills p53-inactivated TNBC cells, highlighting the requirement for MDM2 in TNBC cell survival and as a new therapeutic target for this disease. See related commentary by Peuget and Selivanova, p. 1043. This article is highlighted in the In This Issue feature, p. 1027.","journal":"Cancer Discovery","year":2023,"id":316235,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":110,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9491,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":280679,"name":"Ramkrishna Mitra","orcid":"0000-0002-6181-9066","position":1,"is_corresponding":false},{"id":1019650,"name":"You‐Cai Xiao","orcid":"0000-0003-4942-4501","position":2,"is_corresponding":false},{"id":1019651,"name":"Peter Michener","orcid":"0000-0002-2425-406X","position":3,"is_corresponding":false},{"id":249116,"name":"Juan Palazzo","orcid":"0000-0003-4462-4790","position":4,"is_corresponding":false},{"id":1019652,"name":"Allen Chao","orcid":"0000-0002-8813-3072","position":5,"is_corresponding":false},{"id":1019653,"name":"Jitendra Gour","orcid":"0000-0003-0125-2253","position":6,"is_corresponding":false},{"id":348572,"name":"Joel Cassel","orcid":"0000-0001-8465-8739","position":7,"is_corresponding":false},{"id":348575,"name":"Joseph M. Salvino","orcid":"0000-0002-2184-5980","position":8,"is_corresponding":false},{"id":280681,"name":"Christine M. Eischen","orcid":"0000-0003-4618-8996","position":9,"is_corresponding":false},{"id":482612,"name":"Clare M. Adams","orcid":"0000-0002-9940-3795","position":0,"is_corresponding":true}],"reference_count":90,"raw_metadata":null,"created_at":"2026-07-19T01:06:38.213358Z","pmid":"36734633","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}