Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity.
Nat Commun
; 13(1): 5345, 2022 09 15.
Article
in En
| MEDLINE
| ID: mdl-36109521
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
E2F1 Transcription Factor
/
Prostatic Neoplasms, Castration-Resistant
Type of study:
Prognostic_studies
Limits:
Humans
/
Male
Language:
En
Journal:
Nat Commun
Journal subject:
BIOLOGIA
/
CIENCIA
Year:
2022
Document type:
Article
Affiliation country: