FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4379160717> ?p ?o ?g. }

• W4379160717 endingPage "B004" @default.
• W4379160717 startingPage "B004" @default.
• W4379160717 abstract "Abstract Background: Metastatic prostate cancer (mPC) is notable for a spectrum of recurrent genomic alterations, some associated with overall prognosis and others predicting response to specific therapeutics. Standard mPC interventions are designed to suppress the signaling program regulated by the androgen receptor (AR). These include androgen deprivation therapy (ADT) to reduce AR ligand levels and AR signaling inhibitors (ARSI) that directly impair AR function. While ADT and ARSI produce clinical responses in most patients, the duration and depth of response vary greatly. In addition, specific recurring genomic alterations are associated with shorter responses after ADT and ARSI therapy. Among these are mutations and/or genomic copy loss involving key tumor suppressor genes, including PTEN, RB1 and TP53. However, the mechanistic contribution of TP53 loss to AR signaling and resistance to AR pathway-directed therapy remains unresolved. Methods: Isogenic prostate cancer cell lines with intact and TP53 deletions were constructed using CRISPR/Cas9. The transcriptome profiles were determined by RNA-seq, and ChIP-seq was used to determine the chromatin landscapes of AR localization. In addition, we performed ATAC-seq to assess chromatin accessibility. Finally, to further validate the findings, we comprehensively analyzed AR-regulated gene expression and AR cistromes across a panel of patient-derived xenograft (PDX) models and clinical cohorts of mPC patient samples with respect to TP53 status. Results: Compared to TP53-wild-type (WT) cells, the transcriptional results of isogenic knockout TP53 lines showed impaired AR canonical activity. However, the downregulated AR response pathway is not caused by reduced levels of AR transcript or protein levels. Additionally, a similar trend was also found while comparing TP53-WT PDX models with TP53-loss models. We found that the loss of TP53 can shift the chromatin binding of AR, and the altered AR binding sites correlated with genes involved in neurogenesis pathways, which provide a potential mechanism of how the loss of TP53 might impact AR signaling and promote ADT and ARSI treatment resistance. We also identified additional AR chromatin binding sites that were enriched due to the loss of TP53. The targets potentially regulated by these sites are involved in multiple pathways, including cell morphogenesis involved in differentiation and response to the endogenous stimulus. Conclusions and Future Directions: Overall, the results indicate that in addition to altering DNA damage and repair pathways and contributing to cancer progression, genetic loss of TP53 in mPC may directly impair ADT and ARSI therapies, partially through alteration of AR chromatin activity. In addition, the AR cistrome reprogramming resulting from TP53 loss could also affect other pathways that could be exploited to overcome ARSI treatment resistance. Citation Format: Wanting Han, Michael D. Nyquist, Ilsa Coleman, Navonil De Sarkar, Lisa Ang, Eva Corey, Peter S. Nelson. Genomic loss of TP53 impairs AR-targeted activity in metastatic prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B004." @default.
• W4379160717 created "2023-06-03" @default.
• W4379160717 creator A5010259733 @default.
• W4379160717 creator A5018745405 @default.
• W4379160717 creator A5030953346 @default.
• W4379160717 creator A5067800417 @default.
• W4379160717 creator A5076980825 @default.
• W4379160717 creator A5079009669 @default.
• W4379160717 creator A5079338108 @default.
• W4379160717 date "2023-06-02" @default.
• W4379160717 modified "2023-10-17" @default.
• W4379160717 title "Abstract B004: Genomic loss of TP53 impairs AR-targeted activity in metastatic prostate cancer" @default.
• W4379160717 doi "https://doi.org/10.1158/1538-7445.prca2023-b004" @default.
• W4379160717 hasPublicationYear "2023" @default.
• W4379160717 type Work @default.
• W4379160717 citedByCount "0" @default.
• W4379160717 crossrefType "journal-article" @default.
• W4379160717 hasAuthorship W4379160717A5010259733 @default.
• W4379160717 hasAuthorship W4379160717A5018745405 @default.
• W4379160717 hasAuthorship W4379160717A5030953346 @default.
• W4379160717 hasAuthorship W4379160717A5067800417 @default.
• W4379160717 hasAuthorship W4379160717A5076980825 @default.
• W4379160717 hasAuthorship W4379160717A5079009669 @default.
• W4379160717 hasAuthorship W4379160717A5079338108 @default.
• W4379160717 hasConcept C104317684 @default.
• W4379160717 hasConcept C121608353 @default.
• W4379160717 hasConcept C126322002 @default.
• W4379160717 hasConcept C150194340 @default.
• W4379160717 hasConcept C154456304 @default.
• W4379160717 hasConcept C162317418 @default.
• W4379160717 hasConcept C2777609662 @default.
• W4379160717 hasConcept C2777899217 @default.
• W4379160717 hasConcept C2780192828 @default.
• W4379160717 hasConcept C502942594 @default.
• W4379160717 hasConcept C530470458 @default.
• W4379160717 hasConcept C54355233 @default.
• W4379160717 hasConcept C61367390 @default.
• W4379160717 hasConcept C62478195 @default.
• W4379160717 hasConcept C71924100 @default.
• W4379160717 hasConcept C83640560 @default.
• W4379160717 hasConcept C86554907 @default.
• W4379160717 hasConcept C86803240 @default.
• W4379160717 hasConcept C98108389 @default.
• W4379160717 hasConceptScore W4379160717C104317684 @default.
• W4379160717 hasConceptScore W4379160717C121608353 @default.
• W4379160717 hasConceptScore W4379160717C126322002 @default.
• W4379160717 hasConceptScore W4379160717C150194340 @default.
• W4379160717 hasConceptScore W4379160717C154456304 @default.
• W4379160717 hasConceptScore W4379160717C162317418 @default.
• W4379160717 hasConceptScore W4379160717C2777609662 @default.
• W4379160717 hasConceptScore W4379160717C2777899217 @default.
• W4379160717 hasConceptScore W4379160717C2780192828 @default.
• W4379160717 hasConceptScore W4379160717C502942594 @default.
• W4379160717 hasConceptScore W4379160717C530470458 @default.
• W4379160717 hasConceptScore W4379160717C54355233 @default.
• W4379160717 hasConceptScore W4379160717C61367390 @default.
• W4379160717 hasConceptScore W4379160717C62478195 @default.
• W4379160717 hasConceptScore W4379160717C71924100 @default.
• W4379160717 hasConceptScore W4379160717C83640560 @default.
• W4379160717 hasConceptScore W4379160717C86554907 @default.
• W4379160717 hasConceptScore W4379160717C86803240 @default.
• W4379160717 hasConceptScore W4379160717C98108389 @default.
• W4379160717 hasIssue "11_Supplement" @default.
• W4379160717 hasLocation W43791607171 @default.
• W4379160717 hasOpenAccess W4379160717 @default.
• W4379160717 hasPrimaryLocation W43791607171 @default.
• W4379160717 hasRelatedWork W1602913332 @default.
• W4379160717 hasRelatedWork W2023591758 @default.
• W4379160717 hasRelatedWork W2092268174 @default.
• W4379160717 hasRelatedWork W2142008762 @default.
• W4379160717 hasRelatedWork W2488918559 @default.
• W4379160717 hasRelatedWork W2988201157 @default.
• W4379160717 hasRelatedWork W4295745228 @default.
• W4379160717 hasRelatedWork W4297956145 @default.
• W4379160717 hasRelatedWork W4361239121 @default.
• W4379160717 hasRelatedWork W16813516 @default.
• W4379160717 hasVolume "83" @default.
• W4379160717 isParatext "false" @default.
• W4379160717 isRetracted "false" @default.
• W4379160717 workType "article" @default.