Transcriptional profiling identifies an androgen receptor activity-low, stemness program associated with enzalutamide resistance

Joshi J. Alumkal, Duanchen Sun, Eric Lu, Tomasz M. Beer, George V. Thomas, Emile Latour, Rahul Aggarwal, Jeremy Cetnar, Charles J. Ryan, Shaadi Tabatabaei, Shawna Bailey, Claire B. Turina, David A. Quigley, Xiangnan Guan, Adam Foye, Jack F. Youngren, Joshua Urrutia, Jiaoti Huangi, Alana S. Weinstein, Verena FriedlMatthew Rettig, Robert E. Reiter, Daniel E. Spratt, Martin Gleav, Christopher P. Evans, Joshua M. Stuart, Yiyi Chen, Felix Y. Feng, Eric J. Small, Owen N. Witte, Zheng Xia

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

The androgen receptor (AR) antagonist enzalutamide is one of the principal treatments for men with castration-resistant prostate cancer (CRPC). However, not all patients respond, and resistance mechanisms are largely unknown. We hypothesized that genomic and transcriptional features from metastatic CRPC biopsies prior to treatment would be predictive of de novo treatment resistance. To this end, we conducted a phase II trial of enzalutamide treatment (160 mg/d) in 36 men with metastatic CRPC. Thirty-four patients were evaluable for the primary end point of a prostate-specific antigen (PSA)50 response (PSA decline ≥50% at 12 wk vs. baseline). Nine patients were classified as nonresponders (PSA decline <50%), and 25 patients were classified as responders (PSA decline ≥50%). Failure to achieve a PSA50 was associated with shorter progression-free survival, time on treatment, and overall survival, demonstrating PSA50's utility. Targeted DNA-sequencing was performed on 26 of 36 biopsies, and RNA-sequencing was performed on 25 of 36 biopsies that contained sufficient material. Using computational methods, we measured AR transcriptional function and performed gene set enrichment analysis (GSEA) to identify pathways whose activity state correlated with de novo resistance. TP53 gene alterations were more common in nonresponders, although this did not reach statistical significance (P = 0.055). AR gene alterations and AR expression were similar between groups. Importantly, however, transcriptional measurements demonstrated that specific gene sets-including those linked to low AR transcriptional activity and a stemness program-were activated in nonresponders. Our results suggest that patients whose tumors harbor this program should be considered for clinical trials testing rational agents to overcome de novo enzalutamide resistance.

Original languageEnglish (US)
Pages (from-to)12315-12323
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number22
DOIs
StatePublished - Jun 2 2020

Keywords

  • Androgen receptor
  • Enzalutamide
  • Resistance
  • Stemness

PubMed: MeSH publication types

  • Clinical Trial
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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  • Cite this

    Alumkal, J. J., Sun, D., Lu, E., Beer, T. M., Thomas, G. V., Latour, E., Aggarwal, R., Cetnar, J., Ryan, C. J., Tabatabaei, S., Bailey, S., Turina, C. B., Quigley, D. A., Guan, X., Foye, A., Youngren, J. F., Urrutia, J., Huangi, J., Weinstein, A. S., ... Xia, Z. (2020). Transcriptional profiling identifies an androgen receptor activity-low, stemness program associated with enzalutamide resistance. Proceedings of the National Academy of Sciences of the United States of America, 117(22), 12315-12323. https://doi.org/10.1073/pnas.1922207117