Loss of SNAI2 in Prostate Cancer Correlates With Clinical Response to Androgen Deprivation Therapy.

Autor:	Cmero M; Department of Surgery, University of Melbourne, Parkville, Victoria, Australia.; Division of Bioinformatics, Walter and Eliza Hall Institute, Parkville, Victoria, Australia.; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia., Kurganovs NJ; Department of Surgery, University of Melbourne, Parkville, Victoria, Australia., Stuchbery R; Department of Surgery, University of Melbourne, Parkville, Victoria, Australia., McCoy P; Department of Surgery, University of Melbourne, Parkville, Victoria, Australia., Grima C; Department of Surgery, University of Melbourne, Parkville, Victoria, Australia., Ngyuen A; Department of Surgery, University of Melbourne, Parkville, Victoria, Australia., Chow K; Department of Surgery, University of Melbourne, Parkville, Victoria, Australia.; Department of Urology, Royal Melbourne Hospital, Parkville, Victoria, Australia., Mangiola S; Department of Surgery, University of Melbourne, Parkville, Victoria, Australia.; Division of Bioinformatics, Walter and Eliza Hall Institute, Parkville, Victoria, Australia., Macintyre G; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom., Howard N; Department of Urology, Royal Melbourne Hospital, Parkville, Victoria, Australia., Kerger M; Department of Urology, Royal Melbourne Hospital, Parkville, Victoria, Australia., Dundee P; Department of Urology, Royal Melbourne Hospital, Parkville, Victoria, Australia.; Department of Urology, Peninsula Health, Frankston, Victoria, Australia., Ruljancich P; Department of Urology, Box Hill Hospital, Box Hill, Victoria, Australia.; Epworth Eastern Hospital, Box Hill, Victoria, Australia., Clarke D; Department of Urology, Royal Melbourne Hospital, Parkville, Victoria, Australia., Grummet J; Department of Urology, Alfred Hospital, Prahan, Victoria, Australia.; Monash University, Clayton, Victoria, Australia., Peters JS; Department of Urology, Royal Melbourne Hospital, Parkville, Victoria, Australia., Costello AJ; Department of Surgery, University of Melbourne, Parkville, Victoria, Australia.; Department of Urology, Royal Melbourne Hospital, Parkville, Victoria, Australia., Norden S; TissuPath, Mount Waverly, Victoria, Australia., Ryan A; TissuPath, Mount Waverly, Victoria, Australia., Parente P; Monash University, Clayton, Victoria, Australia.; Department of Medical Oncology, Box Hill Hospital, Box Hill, Victoria, Australia., Hovens CM; Department of Surgery, University of Melbourne, Parkville, Victoria, Australia.; Department of Urology, Royal Melbourne Hospital, Parkville, Victoria, Australia.; Victorian Comprehensive Cancer Centre, Melbourne, Victoria, Australia., Corcoran NM; Department of Surgery, University of Melbourne, Parkville, Victoria, Australia.; Department of Urology, Royal Melbourne Hospital, Parkville, Victoria, Australia.; Department of Urology, Peninsula Health, Frankston, Victoria, Australia.; Victorian Comprehensive Cancer Centre, Melbourne, Victoria, Australia.
Jazyk:	angličtina
Zdroj:	JCO precision oncology [JCO Precis Oncol] 2021 Jun 22; Vol. 5. Date of Electronic Publication: 2021 Jun 22 (Print Publication: 2021).
DOI:	10.1200/PO.20.00337
Abstrakt:	Purpose: Androgen receptor (AR) signaling is important in prostate cancer progression, and therapies that target this pathway have been the mainstay of treatment for advanced disease for over 70 years. Tumors eventually progress despite castration through a number of well-characterized mechanisms; however, little is known about what determines the magnitude of response to short-term pathway inhibition. Methods: We evaluated a novel combination of AR-targeting therapies (degarelix, abiraterone, and bicalutamide) and noted that the objective patient response to therapy was highly variable. To investigate what was driving treatment resistance in poorly responding patients, as a secondary outcome we comprehensively characterized pre- and post-treatment samples using both whole-genome and RNA sequencing. Results: We find that resistance following short-term treatment differs molecularly from typical progressive castration-resistant disease, associated with transcriptional reprogramming, to a transitional epithelial-to-mesenchymal transition (EMT) phenotype rather than an upregulation of AR signaling. Unexpectedly, tolerance to therapy appears to be the default state, with treatment response correlating with the prevalence of tumor cells deficient for SNAI2 , a key regulator of EMT reprogramming. Conclusion: We show that EMT characterizes acutely resistant prostate tumors and that deletion of SNAI2 , a key transcriptional regulator of EMT, correlates with clinical response. Competing Interests: Geoff Macintyre Stock and Other Ownership Interests: Tailor Bio Ltd Uncompensated Relationships: Tailor Bio Ltd Jeremy Grummet Stock and Other Ownership Interests: MRI PRO Pty Ltd Honoraria: BK Ultrasound, Biobot, Mundipharma Travel, Accommodations, Expenses: Astellas Pharma Christopher M. Hovens Patents, Royalties, Other Intellectual Property: past patents in unrelated field Niall M. Corcoran Research Funding: Janssen Oncology No other potential conflicts of interest were reported.Geoff Macintyre Stock and Other Ownership Interests: Tailor Bio Ltd Uncompensated Relationships: Tailor Bio Ltd Jeremy Grummet Stock and Other Ownership Interests: MRI PRO Pty Ltd Honoraria: BK Ultrasound, Biobot, Mundipharma Travel, Accommodations, Expenses: Astellas Pharma Christopher M. Hovens Patents, Royalties, Other Intellectual Property: past patents in unrelated field Niall M. Corcoran Research Funding: Janssen Oncology No other potential conflicts of interest were reported. (© 2021 by American Society of Clinical Oncology.)
Databáze:	MEDLINE
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