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.
View: Text | PDF
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

×

Figure 3

A putative enhancer downstream of AR is amplified after ARSI therapy.

Options: View larger image (or click on image) Download as PowerPoint
A putative enhancer downstream of AR is amplified after ARSI therapy. (A...
(A) Overlaying multiomics sequencing data revealed potential functional elements (C1–C4) flanking AR associated with ARSI resistance. enh, the known enhancer upstream of AR reported by Quigley et al. (5); prom, AR promoter; C1–C4, candidate functional elements (C1: chrX: 67043000-67046000; C2: chrX: 67104300-67106900; C3: chrX: 67746500-67748100; C4: chrX: 67787800-67793300; hg38); rHMR, recurrent hypomethylated regions in 100 mCRPC biopsies identified using WGBS reported by Zhao et al. (36) (redness indicates the frequency of recurrence); #dup, total number of TD events overlapping each base pair, identified by WGS of 201 mCRPC biopsies (n = 156 WCDT and n = 45 HMF samples); #dup new, total number of TD events overlapping each base pair, newly emerging after progression of disease on ARSIs, identified by WGS of 45 paired mCRPC biopsies; CN sum, copy number per base pair summed over the 201 mCRPC biopsies; CN gain, copy number gain (after ARSI – before ARSI) summed over the 45 paired mCRPC biopsies. Bottom 4 tracks show ChIP-Seq data for AR, FOXA1, HOXB13, and H3K27ac generated in normal prostate epithelium, primary PCa, and mCRPC, respectively (37). (B) HiChIP of H3K27ac in LNCaP cells (data were generated by Giambartolomei et al., ref. 40) demonstrates evidence of chromatin looping between C4 and the AR promoter.