Genomic and transcriptomic features of androgen receptor signaling inhibitor resistance in metastatic castration-resistant prostate cancer
Xiaolin Zhu, … , Michiel S. van der Heijden, Felix Y. Feng
Xiaolin Zhu, … , Michiel S. van der Heijden, Felix Y. Feng
Published October 1, 2024
Citation Information: J Clin Invest. 2024;134(19):e178604. https://doi.org/10.1172/JCI178604.
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Genomic and transcriptomic features of androgen receptor signaling inhibitor resistance in metastatic castration-resistant prostate cancer

Abstract

BACKGROUND Androgen 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.METHODS To 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.RESULTS We 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.CONCLUSION Our findings expand the knowledge of ARSI resistance and point out actionable next steps, exemplified by potentially targeting SSTR1, to improve patient outcomes.FUNDING National 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.

Authors

Xiaolin Zhu, Tatyanah Farsh, Daniël Vis, Ivan Yu, Haolong Li, Tianyi Liu, Martin Sjöström, Raunak Shrestha, Jeroen Kneppers, Tesa Severson, Meng Zhang, Arian Lundberg, Thaidy Moreno Rodriguez, Alana S. Weinstein, Adam Foye, Niven Mehra, Rahul R. Aggarwal, Andries M. Bergman, Eric J. Small, Nathan A. Lack, Wilbert Zwart, David A. Quigley, Michiel S. van der Heijden, Felix Y. Feng

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Figure 4

Transcriptomics analyses comparing mCRPC tumors before and after ARSIs.

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Transcriptomics analyses comparing mCRPC tumors before and after ARSIs. ...
(A) Heatmap of the 22 genes used to subtype mCRPC by Labrecque et al. (11), sorted by AR expression. Both extremes of the AR expression spectrum were enriched with ARSI-resistant tumors, indicating diverging changes. ARe, upstream AR enhancer reported by Quigley et al. (5). (B) Scatter plot of AR and NE scores calculated per Beltran et al. (9). Directed line segments indicate the 3 pairs showing a clear post-ARSI phenotypic switch, 2 of which (the 2 WCDT pairs) were also reported by Westbrook et al. (13). All 5 NE-high samples are post-ARSI samples without a high AR copy number. (C) Focused heatmap of the 3 phenotypic converters in B highlights the transcriptional heterogeneity within this group. (D) Unpaired DGE analysis identified relevant genes involved in ARSI-resistant tumors, including LMO3 (a NE TF and 1 of the 22 Labrecque genes) and the Wnt signaling regulator SFRP5 (Wald test, DESeq2). diff, differential. (E) Unpaired DGE analysis of Reactome pathways highlighted that FGFR pathways were among the most upregulated in ARSI-resistant mCRPC (Wilcoxon test). (F) FGFR3 pathway activity was higher in mCRPC tumors with a high NE score (>0.4 as defined by Beltran et al. [ref. 9]; Wilcoxon test) (G) Changes in the FGFR2 pathway and AR expression were anticorrelated.