Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
15 09 2022
15 09 2022
Historique:
received:
14
03
2022
accepted:
11
08
2022
entrez:
15
9
2022
pubmed:
16
9
2022
medline:
20
9
2022
Statut:
epublish
Résumé
The androgen receptor (AR) signaling inhibitor enzalutamide (enza) is one of the principal treatments for metastatic castration-resistant prostate cancer (CRPC). Several emergent enza clinical resistance mechanisms have been described, including lineage plasticity in which the tumors manifest reduced dependency on the AR. To improve our understanding of enza resistance, herein we analyze the transcriptomes of matched biopsies from men with metastatic CRPC obtained prior to treatment and at progression (n = 21). RNA-sequencing analysis demonstrates that enza does not induce marked, sustained changes in the tumor transcriptome in most patients. However, three patients' progression biopsies show evidence of lineage plasticity. The transcription factor E2F1 and pathways linked to tumor stemness are highly activated in baseline biopsies from patients whose tumors undergo lineage plasticity. We find a gene signature enriched in these baseline biopsies that is strongly associated with poor survival in independent patient cohorts and with risk of castration-induced lineage plasticity in patient-derived xenograft models, suggesting that tumors harboring this gene expression program may be at particular risk for resistance mediated by lineage plasticity and poor outcomes.
Identifiants
pubmed: 36109521
doi: 10.1038/s41467-022-32701-6
pii: 10.1038/s41467-022-32701-6
pmc: PMC9477876
doi:
Substances chimiques
Androgen Receptor Antagonists
0
Benzamides
0
E2F1 Transcription Factor
0
Nitriles
0
Receptors, Androgen
0
Phenylthiohydantoin
2010-15-3
RNA
63231-63-0
enzalutamide
93T0T9GKNU
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
5345Subventions
Organisme : NCI NIH HHS
ID : P50 CA097186
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA234715
Pays : United States
Organisme : NHLBI NIH HHS
ID : R21 HL145426
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA163227
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA224079
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA046592
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA251245
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA186786
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009357
Pays : United States
Informations de copyright
© 2022. The Author(s).
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