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Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity.

Publication ,  Journal Article
Westbrook, TC; Guan, X; Rodansky, E; Flores, D; Liu, CJ; Udager, AM; Patel, RA; Haffner, MC; Hu, Y-M; Sun, D; Beer, TM; Foye, A; Aggarwal, R ...
Published in: Nat Commun
September 15, 2022

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.

Duke Scholars

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Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

September 15, 2022

Volume

13

Issue

1

Start / End Page

5345

Location

England

Related Subject Headings

  • Receptors, Androgen
  • RNA
  • Prostatic Neoplasms, Castration-Resistant
  • Phenylthiohydantoin
  • Nitriles
  • Male
  • Humans
  • E2F1 Transcription Factor
  • Drug Resistance, Neoplasm
  • Cell Line, Tumor
 

Citation

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MLA
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Westbrook, T. C., Guan, X., Rodansky, E., Flores, D., Liu, C. J., Udager, A. M., … Alumkal, J. J. (2022). Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity. Nat Commun, 13(1), 5345. https://doi.org/10.1038/s41467-022-32701-6
Westbrook, Thomas C., Xiangnan Guan, Eva Rodansky, Diana Flores, Chia Jen Liu, Aaron M. Udager, Radhika A. Patel, et al. “Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity.Nat Commun 13, no. 1 (September 15, 2022): 5345. https://doi.org/10.1038/s41467-022-32701-6.
Westbrook TC, Guan X, Rodansky E, Flores D, Liu CJ, Udager AM, et al. Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity. Nat Commun. 2022 Sep 15;13(1):5345.
Westbrook, Thomas C., et al. “Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity.Nat Commun, vol. 13, no. 1, Sept. 2022, p. 5345. Pubmed, doi:10.1038/s41467-022-32701-6.
Westbrook TC, Guan X, Rodansky E, Flores D, Liu CJ, Udager AM, Patel RA, Haffner MC, Hu Y-M, Sun D, Beer TM, Foye A, Aggarwal R, Quigley DA, Youngren JF, Ryan CJ, Gleave M, Wang Y, Huang J, Coleman I, Morrissey C, Nelson PS, Evans CP, Lara P, Reiter RE, Witte O, Rettig M, Wong CK, Weinstein AS, Uzunangelov V, Stuart JM, Thomas GV, Feng FY, Small EJ, Yates JA, Xia Z, Alumkal JJ. Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity. Nat Commun. 2022 Sep 15;13(1):5345.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

September 15, 2022

Volume

13

Issue

1

Start / End Page

5345

Location

England

Related Subject Headings

  • Receptors, Androgen
  • RNA
  • Prostatic Neoplasms, Castration-Resistant
  • Phenylthiohydantoin
  • Nitriles
  • Male
  • Humans
  • E2F1 Transcription Factor
  • Drug Resistance, Neoplasm
  • Cell Line, Tumor