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Genomic and transcriptomic features of androgen receptor signaling inhibitor resistance in metastatic castration-resistant prostate cancer

Zhu, Xiaolin ; Farsh, Tatyanah ; Vis, Daniël ; Yu, Ivan ; Li, Haolong ; Liu, Tianyi ; Sjöström, Martin LU ; Shrestha, Raunak ; Kneppers, Jeroen and Severson, Tesa , et al. (2024) In The Journal of clinical investigation 134(19).
Abstract

BACKGROUNDAndrogen receptor signaling inhibitors (ARSIs) have improved outcomes for patients with metastatic castration-resistant prostate cancer (mCRPC), but their clinical benefit is limited by treatment resistance.METHODSTo investigate the mechanisms of ARSI resistance, we analyzed the whole-genome (n = 45) and transcriptome (n = 31) sequencing data generated from paired metastatic biopsies obtained before initiation of first-line ARSI therapy for mCRPC and after radiographic disease progression. We investigated the effects of genetic and pharmacologic modulation of SSTR1 in 22Rv1 cells, a representative mCRPC cell line.RESULTSWe confirmed the predominant role of tumor genetic alterations converging on augmenting androgen receptor... (More)

BACKGROUNDAndrogen receptor signaling inhibitors (ARSIs) have improved outcomes for patients with metastatic castration-resistant prostate cancer (mCRPC), but their clinical benefit is limited by treatment resistance.METHODSTo investigate the mechanisms of ARSI resistance, we analyzed the whole-genome (n = 45) and transcriptome (n = 31) sequencing data generated from paired metastatic biopsies obtained before initiation of first-line ARSI therapy for mCRPC and after radiographic disease progression. We investigated the effects of genetic and pharmacologic modulation of SSTR1 in 22Rv1 cells, a representative mCRPC cell line.RESULTSWe confirmed the predominant role of tumor genetic alterations converging on augmenting androgen receptor (AR) signaling and the increased transcriptional heterogeneity and lineage plasticity during the emergence of ARSI resistance. We further identified amplifications involving a putative enhancer downstream of the AR and transcriptional downregulation of SSTR1, encoding somatostatin receptor 1, in ARSI-resistant tumors. We found that patients with SSTR1-low mCRPC tumors derived less benefit from subsequent ARSI therapy in a retrospective cohort. We showed that SSTR1 was antiproliferative in 22Rv1 cells and that the FDA-approved drug pasireotide suppressed 22Rv1 cell proliferation.CONCLUSIONOur findings expand the knowledge of ARSI resistance and point out actionable next steps, exemplified by potentially targeting SSTR1, to improve patient outcomes.FUNDINGNational Cancer Institute (NCI), NIH; Prostate Cancer Foundation; Conquer Cancer, American Society of Clinical Oncology Foundation; UCSF Benioff Initiative for Prostate Cancer Research; Netherlands Cancer Institute.

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type
Contribution to journal
publication status
published
subject
keywords
Male, Humans, Prostatic Neoplasms, Castration-Resistant/genetics, Receptors, Androgen/genetics, Drug Resistance, Neoplasm/genetics, Cell Line, Tumor, Signal Transduction/drug effects, Transcriptome, Neoplasm Metastasis, Receptors, Somatostatin/genetics, Gene Expression Regulation, Neoplastic/drug effects, Androgen Receptor Antagonists/pharmacology, Neoplasm Proteins/genetics
in
The Journal of clinical investigation
volume
134
issue
19
publisher
American Society for Clinical Investigation
external identifiers
  • scopus:85205446966
  • pmid:39352383
ISSN
0021-9738
DOI
10.1172/JCI178604
language
English
LU publication?
no
id
f1e7cce8-c2f4-4ee3-a2ba-096d3386dabe
date added to LUP
2026-02-09 16:47:11
date last changed
2026-02-10 04:02:23
@article{f1e7cce8-c2f4-4ee3-a2ba-096d3386dabe,
  abstract     = {{<p>BACKGROUNDAndrogen receptor signaling inhibitors (ARSIs) have improved outcomes for patients with metastatic castration-resistant prostate cancer (mCRPC), but their clinical benefit is limited by treatment resistance.METHODSTo investigate the mechanisms of ARSI resistance, we analyzed the whole-genome (n = 45) and transcriptome (n = 31) sequencing data generated from paired metastatic biopsies obtained before initiation of first-line ARSI therapy for mCRPC and after radiographic disease progression. We investigated the effects of genetic and pharmacologic modulation of SSTR1 in 22Rv1 cells, a representative mCRPC cell line.RESULTSWe confirmed the predominant role of tumor genetic alterations converging on augmenting androgen receptor (AR) signaling and the increased transcriptional heterogeneity and lineage plasticity during the emergence of ARSI resistance. We further identified amplifications involving a putative enhancer downstream of the AR and transcriptional downregulation of SSTR1, encoding somatostatin receptor 1, in ARSI-resistant tumors. We found that patients with SSTR1-low mCRPC tumors derived less benefit from subsequent ARSI therapy in a retrospective cohort. We showed that SSTR1 was antiproliferative in 22Rv1 cells and that the FDA-approved drug pasireotide suppressed 22Rv1 cell proliferation.CONCLUSIONOur findings expand the knowledge of ARSI resistance and point out actionable next steps, exemplified by potentially targeting SSTR1, to improve patient outcomes.FUNDINGNational Cancer Institute (NCI), NIH; Prostate Cancer Foundation; Conquer Cancer, American Society of Clinical Oncology Foundation; UCSF Benioff Initiative for Prostate Cancer Research; Netherlands Cancer Institute.</p>}},
  author       = {{Zhu, Xiaolin and Farsh, Tatyanah and Vis, Daniël and Yu, Ivan and Li, Haolong and Liu, Tianyi and Sjöström, Martin and Shrestha, Raunak and Kneppers, Jeroen and Severson, Tesa and Zhang, Meng and Lundberg, Arian and Moreno Rodriguez, Thaidy and Weinstein, Alana S and Foye, Adam and Mehra, Niven and Aggarwal, Rahul R and Bergman, Andries M and Small, Eric J and Lack, Nathan A and Zwart, Wilbert and Quigley, David A and van der Heijden, Michiel S and Feng, Felix Y}},
  issn         = {{0021-9738}},
  keywords     = {{Male; Humans; Prostatic Neoplasms, Castration-Resistant/genetics; Receptors, Androgen/genetics; Drug Resistance, Neoplasm/genetics; Cell Line, Tumor; Signal Transduction/drug effects; Transcriptome; Neoplasm Metastasis; Receptors, Somatostatin/genetics; Gene Expression Regulation, Neoplastic/drug effects; Androgen Receptor Antagonists/pharmacology; Neoplasm Proteins/genetics}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{19}},
  publisher    = {{American Society for Clinical Investigation}},
  series       = {{The Journal of clinical investigation}},
  title        = {{Genomic and transcriptomic features of androgen receptor signaling inhibitor resistance in metastatic castration-resistant prostate cancer}},
  url          = {{http://dx.doi.org/10.1172/JCI178604}},
  doi          = {{10.1172/JCI178604}},
  volume       = {{134}},
  year         = {{2024}},
}