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

Autor: Zhu X; Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, USA.; Division of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, California, USA., Farsh T; Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, USA.; Department of Radiation Oncology, UCSF, San Francisco, California, USA., Vis D; Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, Netherlands., Yu I; Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada., Li H; Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, USA.; Department of Radiation Oncology, UCSF, San Francisco, California, USA., Liu T; Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, USA.; Department of Radiation Oncology, UCSF, San Francisco, California, USA., Sjöström M; Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, USA.; Department of Radiation Oncology, UCSF, San Francisco, California, USA., Shrestha R; Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, USA.; Department of Radiation Oncology, UCSF, San Francisco, California, USA., Kneppers J; Division of Oncogenomics, Oncode Institute, Netherlands Cancer Institute, Amsterdam, Netherlands., Severson T; Division of Oncogenomics, Oncode Institute, Netherlands Cancer Institute, Amsterdam, Netherlands., Zhang M; Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, USA.; Department of Radiation Oncology, UCSF, San Francisco, California, USA., Lundberg A; Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, USA.; Department of Radiation Oncology, UCSF, San Francisco, California, USA., Moreno Rodriguez T; Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, USA.; Department of Urology, UCSF, San Francisco, California, USA., Weinstein AS; Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, USA.; Department of Radiation Oncology, UCSF, San Francisco, California, USA., Foye A; Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, USA.; Division of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, California, USA., Mehra N; Department of Medical Oncology, Radboud University Medical Center, Nijmegen, Netherlands., Aggarwal RR; Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, USA.; Division of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, California, USA., Bergman AM; Division of Oncogenomics, Oncode Institute, Netherlands Cancer Institute, Amsterdam, Netherlands., Small EJ; Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, USA.; Division of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, California, USA., Lack NA; Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.; Koç University School of Medicine, Istanbul, Turkey.; Koç University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey., Zwart W; Division of Oncogenomics, Oncode Institute, Netherlands Cancer Institute, Amsterdam, Netherlands., Quigley DA; Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, USA.; Department of Urology, UCSF, San Francisco, California, USA., van der Heijden MS; Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, Netherlands., Feng FY; Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, USA.; Department of Radiation Oncology, UCSF, San Francisco, California, USA.
Jazyk: angličtina
Zdroj: The Journal of clinical investigation [J Clin Invest] 2024 Aug 13; Vol. 134 (19). Date of Electronic Publication: 2024 Aug 13.
DOI: 10.1172/JCI178604
Abstrakt: 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.
Databáze: MEDLINE