Molecular Profile Changes in Patients with Castrate-Resistant Prostate Cancer Pre- and Post-Abiraterone/Prednisone Treatment

Hugues Sicotte, Krishna R. Kalari, Sisi Qin, Scott M. Dehm, Vipul Bhargava, Michael Gormley, Winston Tan, Jason P. Sinnwell, David W. Hillman, Ying Li, Peter T. Vedell, Rachel E. Carlson, Alan H. Bryce, Raphael E. Jimenez, Richard M. Weinshilboum, Manish Kohli, Liewei Wang

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


We identified resistance mechanisms to abiraterone acetate/prednisone (AA/P) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the Prostate Cancer Medically Optimized Genome-Enhanced Therapy (PROMOTE) study. We analyzed whole-exome sequencing (WES) and RNA-sequencing data from 83 patients with metastatic biopsies before (V1) and after 12 weeks of AA/P treatment (V2). Resistance was determined by time to treatment change (TTTC). At V2, 18 and 11 of 58 patients had either short-term (median 3.6 months; range 1.4-4.5) or long-term (median 29 months; range 23.5-41.7) responses, respectively. Nonresponders had low expression of TGFBR3 and increased activation of the Wnt pathway, cell cycle, upregulation of AR variants, both pre- and posttreatment, with further deletion of AR inhibitor CDK11B posttreatment. Deletion of androgen processing genes, HSD17B11, CYP19A1 were observed in nonresponders posttreatment. Genes involved in cell cycle, DNA repair, Wnt-signaling, and Aurora kinase pathways were differentially expressed between the responder and nonresponder at V2. Activation of Wnt signaling in nonresponder and deactivation of MYC or its target genes in responders was detected via SCN loss, somatic mutations, and transcriptomics. Upregulation of genes in the AURKA pathway are consistent with the activation of MYC regulated genes in nonresponders. Several genes in the AKT1 axis had increased mutation rate in nonresponders. We also found evidence of resistance via PDCD1 overexpression in responders. Implications: Finally, we identified candidates drugs to reverse AA/P resistance: topoisomerase inhibitors and drugs targeting the cell cycle via the MYC/AURKA/AURKB/TOP2A and/or PI3K_AKT_MTOR pathways.

Original languageEnglish (US)
Pages (from-to)1739-1750
Number of pages12
JournalMolecular Cancer Research
Issue number12
StatePublished - Dec 2022

Bibliographical note

Publisher Copyright:
©2022 The Authors; Published by the American Association for Cancer Research.


  • Male
  • Humans
  • Prednisone/therapeutic use
  • Prostatic Neoplasms, Castration-Resistant/drug therapy
  • Aurora Kinase A
  • Antineoplastic Combined Chemotherapy Protocols/therapeutic use
  • Abiraterone Acetate/adverse effects

PubMed: MeSH publication types

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


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