Neoadjuvant-Intensive Androgen Deprivation Therapy Selects for Prostate Tumor Foci with Diverse Subclonal Oncogenic Alterations

Abstract

Primary prostate cancer can have extensive microheterogeneity, but its contribution to the later emergence of metastatic castration-resistant prostate cancer (mCRPC) remains unclear. In this study, we microdissected residual prostate cancer foci in radical prostatectomies from 18 men treated with neoadjuvant-intensive androgen deprivation therapy (leuprolide, abiraterone acetate, and prednisone) and analyzed them for resistance mechanisms. Transcriptome profiling showed reduced but persistent androgen receptor (AR) activity in residual tumors, with no increase in neuroendocrine differentiation. Proliferation correlated negatively with AR activity but positively with decreased RB1 expression, and whole-exome sequencing (WES) further showed enrichment for RB1 genomic loss. In 15 cases where 2 or 3 tumor foci were microdissected, WES confirmed a common clonal origin but identified multiple oncogenic alterations unique to each focus. These findings show that subclones with oncogenic alterations found in mCRPC are present in primary prostate cancer and are selected for by neoadjuvant-intense androgen deprivation therapy. In particular, this study indicates that subclonal RB1 loss may be more common than previously appreciated in intermediate- to high-risk primary prostate cancer and may be an early event, independent of neuroendocrine differentiation, in the development of mCRPC. Comprehensive molecular analyses of primary prostate cancer may detect aggressive subclones and possibly inform adjuvant strategies to prevent recurrence. Neoadjuvant androgen deprivation therapy for prostate cancer selects for tumor foci with subclonal genomic alterations, which may comprise the origin of metastatic castration-resistant prostate cancer. .

MicroRNA-194 promotes lineage plasticity in advanced prostate cancer

“…Amongst other robust associations, one striking finding was that miR-194 activity was strongly inversely correlated with AR signalling across all cohorts examined (Figure 2A; Supplementary Table S5). This observation was validated using a more refined set of AR target genes ( Figure 2B) recently generated by Sowalsky and colleagues (44).…”

“…P and r values were determined using Pearson's correlation tests. (C) Overlap between the miR-194 targetome and an AR target gene set(44). (D) Relative miR-194 expression in LNCaP cells treated with the androgen DHT and AR antagonist Enzalutamide (Enz).…”

Targeting the PI3K/AKT pathway overcomes enzalutamide resistance by inhibiting induction of the glucocorticoid receptor

“…In some respects, high risk localized disease may have similar biology to metastatic HSPC. Upregulation of GR expression has been demonstrated in a subset of patients in both neoadjuvant enzalutamide and neoadjuvant abiraterone/prednisone trials in this setting 33,34 , raising the question of whether adding a PI3K/AKT inhibitor could improve the outcomes for those with HSPC. One explanation for the prevalence of GR expression in these early phase studies, as opposed to well-characterized genomic alterations (e.g.…”

MEIS1 down-regulation by MYC mediates prostate cancer development through elevated HOXB13 expression and AR activity

“…DISCUSSION In many cancer types, the role of amplified MYC in mediating tumorigenesis has been linked to genes involved in ribosomal biogenesis, universally upregulated transcription, proliferation, and reprogramming cells to a pluripotent state [47]. A subset of advanced prostate cancers also harbor amplified MYC, but it is distinct from the upregulated MYC that is a hallmark of many localized prostate cancers [3,[14][15][16]]. In the current study, we used transcriptome profiling to assess subpopulations of prostate tumors based on differential MYC protein expression and MYC activity, and we similarly compared differentially expressed genes and pathways within the larger prostate TCGA cohort based on MYC activity.…”

“…In localized prostate cancers, up-regulated MYC has been further associated with alterations in nucleoli structure, concomitant with increased biogenesis of ribosomal RNA, increased purine metabolism and expression of the telomere RNA subunit TERC [12][13][14]. These effects contrast sharply with the phenotype of highly amplified MYC, which is enriched in metastatic and treatment-resistant prostate cancers, and mirrors the role of MYC in other cancer types via effects on AKT to contribute towards cell division and survival [15][16][17].…”