Identification of Transcription Factor Relationships Associated with Androgen Deprivation Therapy Response and Metastatic Progression in Prostate Cancer

Background: Patients with locally advanced or recurrent prostate cancer typically undergo androgen deprivation therapy (ADT), but the benefits are often short-lived, and responses are variable. ADT failure results in castration-resistant prostate cancer (CRPC), that inevitably leads to metastasis. We hypothesized that differences in tumor transcriptional programs may reflect differential responses to ADT and subsequent metastasis. Results: We performed whole transcriptome analysis of 20 patient-matched Pre-ADT biopsies and 20 Post-ADT prostatectomy specimens, and identified two subgroups of patients (high impact and low impact groups) that exhibited distinct transcriptional changes in response to ADT. We found that all patients lost AR-dependent subtype (PCS2) transcriptional signatures. The high impact group maintained the more aggressive subtype (PCS1) signal, while the low impact group more resembled an AR-suppressed (PCS3) subtype. Computational analyses identified transcription factor coordinated groups (TFCGs) enriched in the high impact group network. Leveraging a large public dataset of over 800 metastatic and primary samples, we identified 33 TFCGs in common between high impact group and metastatic lesions, including SOX4/FOXA2/GATA4, ERF/ETV5/ETV3/ELF4, and a TFCG containing JUN, JUNB, JUND, FOS, FOSB, and FOSL1. The majority of metastatic TFCGs were subsets of larger TFCGs in the high impact group network, suggesting refinement of critical TFCGs in prostate cancer progression. Conclusions: We have identified TFCGs associated with pronounced initial transcriptional response to ADT, aggressive signatures, and metastasis. Our findings suggest multiple new hypotheses that could lead to novel combination therapies to prevent development of CRPC following ADT. Overall design: Sequence alignment and gene level expression quantifications were obtained using the STAR read aligner. We obtained an average of 91,077,364 reads (sd: 41,923,139) with a mean transcriptome coverage of 64x (83% mapping to exons).

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Sharma NV, Pellegrini KL, Ouellet V, Giuste FO, Ramalingam S, Watanabe K, Adam-Granger E, Fossouo L, You S, Freeman MR, Vertino P, Conneely K, Osunkoya AO, Trudel D, Mes-Masson AM, Petros JA, Saad F, Moreno CS