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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Clinical Research and Public Health Oncology

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 2

The AR locus is the major genetic substrate of converging evolution under ARSI-induced selective pressure.

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The AR locus is the major genetic substrate of converging evolution unde...
(A) Amplification of AR and its flanking sequences stood out as the predominant signal in genome-wide copy number analysis. The human genome was partitioned into 1 kb consecutive bins, and association tests were performed for each bin against the null hypotheses of (a) no pair gaining 1 or more copies after progression on ARSIs (top panel) and (b) no pair losing 1 or more copies thereof (bottom panel), respectively. P values were calculated using the paired Wilcoxon test for the 45 WGS pairs. x axis: chromosomal location with chromosomes numbered; y axis: –log10 (P value). Each dot represents an association test P value (–log10-transformed) for a given genomic bin, and 2 alternating colors (gray and black) were used to facilitate the visualization of genomic bins of consecutive chromosomes. The blue horizontal line in each panel indicates the threshold of nominal statistical significance (P < 0.05) to aid the visualization of potential hits. The AR locus (AR gene ±1 Mb flanking regions) is labeled in green. (B and C) mCRPC continues to acquire additional copies of AR and its upstream enhancer, reported by Quigley et al. (5), while developing ARSI resistance. P values were calculated using the paired Wilcoxon test (n = 45). (D) Copy number gains of AR and its upstream enhancer were highly correlated. (E and F) Higher AR and upstream enhancer copy numbers were correlated with higher AR mRNA levels.