Matches in SemOpenAlex for { <https://semopenalex.org/work/W4361827292> ?p ?o ?g. }
Showing items 1 to 74 of
74
with 100 items per page.
- W4361827292 abstract "<div>Abstract<p>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 <i>in vivo</i>, 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.</p>Significance:<p>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.</p></div>" @default.
- W4361827292 created "2023-04-05" @default.
- W4361827292 creator A5016122970 @default.
- W4361827292 creator A5016268548 @default.
- W4361827292 creator A5020620129 @default.
- W4361827292 creator A5022731013 @default.
- W4361827292 creator A5024095283 @default.
- W4361827292 creator A5027826985 @default.
- W4361827292 creator A5033996966 @default.
- W4361827292 creator A5044366210 @default.
- W4361827292 creator A5058045772 @default.
- W4361827292 creator A5066519998 @default.
- W4361827292 date "2023-03-31" @default.
- W4361827292 modified "2023-09-28" @default.
- W4361827292 title "Data from Targeted MDM2 Degradation Reveals a New Vulnerability for p53-Inactivated Triple-Negative Breast Cancer" @default.
- W4361827292 doi "https://doi.org/10.1158/2159-8290.c.6515061.v1" @default.
- W4361827292 hasPublicationYear "2023" @default.
- W4361827292 type Work @default.
- W4361827292 citedByCount "0" @default.
- W4361827292 crossrefType "posted-content" @default.
- W4361827292 hasAuthorship W4361827292A5016122970 @default.
- W4361827292 hasAuthorship W4361827292A5016268548 @default.
- W4361827292 hasAuthorship W4361827292A5020620129 @default.
- W4361827292 hasAuthorship W4361827292A5022731013 @default.
- W4361827292 hasAuthorship W4361827292A5024095283 @default.
- W4361827292 hasAuthorship W4361827292A5027826985 @default.
- W4361827292 hasAuthorship W4361827292A5033996966 @default.
- W4361827292 hasAuthorship W4361827292A5044366210 @default.
- W4361827292 hasAuthorship W4361827292A5058045772 @default.
- W4361827292 hasAuthorship W4361827292A5066519998 @default.
- W4361827292 hasBestOaLocation W43618272922 @default.
- W4361827292 hasConcept C104317684 @default.
- W4361827292 hasConcept C121608353 @default.
- W4361827292 hasConcept C126322002 @default.
- W4361827292 hasConcept C127561419 @default.
- W4361827292 hasConcept C190283241 @default.
- W4361827292 hasConcept C2776192174 @default.
- W4361827292 hasConcept C2780110267 @default.
- W4361827292 hasConcept C2781230642 @default.
- W4361827292 hasConcept C502942594 @default.
- W4361827292 hasConcept C530470458 @default.
- W4361827292 hasConcept C55493867 @default.
- W4361827292 hasConcept C71924100 @default.
- W4361827292 hasConcept C86803240 @default.
- W4361827292 hasConceptScore W4361827292C104317684 @default.
- W4361827292 hasConceptScore W4361827292C121608353 @default.
- W4361827292 hasConceptScore W4361827292C126322002 @default.
- W4361827292 hasConceptScore W4361827292C127561419 @default.
- W4361827292 hasConceptScore W4361827292C190283241 @default.
- W4361827292 hasConceptScore W4361827292C2776192174 @default.
- W4361827292 hasConceptScore W4361827292C2780110267 @default.
- W4361827292 hasConceptScore W4361827292C2781230642 @default.
- W4361827292 hasConceptScore W4361827292C502942594 @default.
- W4361827292 hasConceptScore W4361827292C530470458 @default.
- W4361827292 hasConceptScore W4361827292C55493867 @default.
- W4361827292 hasConceptScore W4361827292C71924100 @default.
- W4361827292 hasConceptScore W4361827292C86803240 @default.
- W4361827292 hasLocation W43618272921 @default.
- W4361827292 hasLocation W43618272922 @default.
- W4361827292 hasOpenAccess W4361827292 @default.
- W4361827292 hasPrimaryLocation W43618272921 @default.
- W4361827292 hasRelatedWork W1966181922 @default.
- W4361827292 hasRelatedWork W2345782301 @default.
- W4361827292 hasRelatedWork W2400857591 @default.
- W4361827292 hasRelatedWork W4307337217 @default.
- W4361827292 hasRelatedWork W4319058454 @default.
- W4361827292 hasRelatedWork W4361821475 @default.
- W4361827292 hasRelatedWork W4361827292 @default.
- W4361827292 hasRelatedWork W4362541917 @default.
- W4361827292 hasRelatedWork W4368366245 @default.
- W4361827292 hasRelatedWork W4376118236 @default.
- W4361827292 isParatext "false" @default.
- W4361827292 isRetracted "false" @default.
- W4361827292 workType "article" @default.