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

AI Article Synopsis

  • Androgen receptor signaling inhibitors (ARSIs) have improved the treatment of metastatic castration-resistant prostate cancer (mCRPC), but many patients develop resistance to these therapies over time.
  • Researchers analyzed genetic and transcriptomic changes in tumors before and after ARSI treatment to understand the underlying mechanisms of this resistance.
  • They found that alterations enhancing androgen receptor signaling and low levels of somatostatin receptor 1 (SSTR1) are linked to reduced therapy effectiveness, suggesting that targeting SSTR1 could be a potential strategy to improve outcomes for mCRPC patients.

Article 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 (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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11444163PMC
http://dx.doi.org/10.1172/JCI178604DOI Listing

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