Abstract 2415: Genome-wide alterations in gene expression of prostate cancer (PC) cells surviving neo-adjuvant androgen deprivation therapy

AbstractAndrogen deprivation therapy (ADT) is a mainstay of prostate cancer treatment, given the dependence of prostate cells on androgen and the androgen receptor (AR). However, tumors become ADT-resistant, and there is a need to understand the mechanism. One possible mechanism is the upregulation of AR co-regulators, although only a handful have been definitively linked to disease. We previously identified the Mediator subunit MED19 as an AR co-regulator, and reported that MED19 depletion inhibits AR transcriptional activity and growth of androgen-insensitive LNCaP-abl cells. Therefore, we proposed that MED19 upregulation would promote AR activity and drive androgen-independent growth. Here, we show that stable overexpression of MED19 in androgen-dependent LNCaP cells promotes growth under conditions of androgen deprivation. To delineate the mechanism, we determined the MED19 and AR transcriptomes and cistromes in control and MED19 LNCaP cells. We also examined H3K27 acetylation genome-wide. MED19 overexpression selectively alters AR occupancy, H3K27 acetylation, and gene expression. Under conditions of androgen deprivation, genes regulated by MED19 and genomic sites occupied by MED19 and AR are enriched for ELK1, a transcription factor that binds the AR N-terminus to promote select AR-target gene expression. Strikingly, MED19 upregulates expression of monoamine oxidase A (MAOA), a factor that promotes prostate cancer growth. MAOA depletion reduces androgen-independent growth. MED19 and AR occupy the MAOA promoter, with MED19 overexpression enhancing AR occupancy and H3K27 acetylation. Furthermore, MED19 overexpression increases ELK1 occupancy at the MAOA promoter, and ELK1 depletion reduces MAOA expression and androgen-independent growth. This suggests that MED19 cooperates with ELK1 to regulate AR occupancy and H3K27 acetylation at MAOA, upregulating its expression and driving androgen independence in prostate cancer cells. This study provides important insight into the mechanisms of prostate cancer cell growth under low androgen, and underscores the importance of the MED19-MAOA axis in this process.Author summaryProstate cancer is one of the most common cancers worldwide, and androgen hormones are essential for prostate cancer growth. Androgens exert their effects through a protein called the androgen receptor (AR), which turns on and off genes that regulate prostate cancer growth. Powerful drugs that block AR action by lowering androgen levels – so-called androgen deprivation therapy - are used to treat prostate cancer patients, and these yield initial success in reducing tumor growth. However, over time, tumors circumvent androgen deprivation therapy and patients relapse; in many cases, this occurs because AR becomes re-activated. The factors responsible for re-activating AR and promoting growth under androgen deprivation are not well understood. Here, we demonstrate that a subunit of the Mediator transcriptional regulatory complex, called MED19, promotes growth of prostate cancer cells under low androgen conditions, mimicking the ability of tumors to grow under androgen deprivation in prostate cancer patients. MED19 promotes androgen-independent growth by working with a transcription factor that interacts with AR, called ELK1, to induce the expression of genes regulated by AR that promote prostate cancer growth. This study provides important insight into how prostate cancer cells can maintain growth under androgen deprivation through MED19.

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Association of androgen receptor signature and RB1, PTEN, TP53 gene expression with clinical outcome in metastatic hormone-sensitive prostate cancer treated with docetaxel and androgen deprivation therapy.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.5069 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 5069-5069

Author(s):

Laura Ferrer-Mileo ◽

Natalia Jiménez ◽

Oscar Reig ◽

Miguel Ángel Climent ◽

Sara Cros ◽

...

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Androgen Receptor ◽

Clinical Outcome ◽

Androgen Deprivation Therapy ◽

Androgen Deprivation ◽

Castration Resistant Prostate Cancer ◽

Mesenchymal Transition ◽

Hormone Sensitive ◽

Low Expression

5069 Background: Androgen deprivation therapy (ADT) with docetaxel or new antiandrogens has demonstrated a survival benefit in metastatic hormone-sensitive prostate cancer (mHSPC). However, treatment selection for individual patients (pts) remains a challenge. We propose that TMPRSS2-ERG and cell plasticity [neuroendocrine (NE), epithelial to mesenchymal transition (EMT)], immune-related, androgen receptor (AR) and tumor suppressor genes (TSG) ( RB1, PTEN and TP53) expression signatures may predict clinical outcome in mHSPC pts treated with ADT+docetaxel. Methods: This is a multicenter retrospective biomarker study performed in mHSPC pts treated with ADT+docetaxel. A customized panel of 184 genes was designed and tested in total mRNA from FFPE tumor samples by nCounter platform (Nanostring Technologies). Expression levels were correlated with castration resistance-free survival (CRPC-FS) (primary endpoint) and overall survival (OS) by Kaplan Meier and multivariate Cox modeling. A predictive modeling approach was performed with Bujar R package to develop a signature able to predict CRPC-FS. R (v.3.6.3) software was used for statistical analyses. Results: 136 pts were included, and 120 of them were eligible. Median age was 66.9 years (range 46.3-83.6). Gleason score was ≥ 8 in 80.8% of pts; 87.5% and 20.8% of pts had bone and visceral metastases, respectively. Median follow-up was 30.7 months (m) (range 5.5-70.6). 76 pts (63.3%) developed castration-resistant prostate cancer (CRPC). Median time to CRPC was 20 m (range 16.9-23.1) and median OS was not reached. High AR-signature expression independently correlated with longer CRPC-FS (HR 0.4, 95% CI 0.2-0.7, p = 0.003). Considering AR-signature individual gene expression, ARV7 was independently associated with shorter CRPC-FS (HR 1.7, 95% CI 1.2-2.4, p = 0.003). Low expression of all TSG ( PTEN, RB1 and TP53) independently correlated with shorter CRPC-FS (HR 0.3, 95% CI 0.2-0.7, p = 0.003) and OS (HR 0.2, 95% CI 0.1-0.5, p < 0.001). Similarly, low expression of 2 out of the 3 TSG genes or only RB1 plus PTEN were also independently associated with shorter CRPC-FS (HR 0.5, 95% CI 0.3-0.9, p = 0.015; HR 0.4, 95% CI 0.2-0.7, p = 0.003, respectively) and OS (HR 0.4, 95% CI 0.2-0.9, p = 0.027; HR 0.2, 95% CI 0.1-0.6, p = 0.001, respectively). TMPRSS2-ERG expression, NE, EMT and immune-related signatures were not associated with clinical outcome. Bujar analysis defined a 17-gene signature (including ARV7, RB1, PTEN, BRCA2 and ATM) that was able to discriminate pts at different risk of developing early CRPC. Conclusions: High AR-signature expression correlates with a longer CRPC-FS while ARV7 expression is associated with shorter CRPC-FS. Low expression of TSG is associated with an aggressive clinical evolution in mHSPC pts treated with ADT+taxanes.

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Genome-wide alterations in gene expression of prostate cancer (PC) cells surviving neoadjuvant androgen deprivation therapy (ADT).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.88 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 88-88

Author(s):

Anna C. Ferrari ◽

Ying Chen ◽

Hatem E. Sabaawy ◽

Mark N. Stein ◽

David Foran ◽

...

Keyword(s):

Gene Expression ◽

Androgen Deprivation Therapy ◽

Unsaturated Fatty Acids ◽

R Package ◽

Tumor Burden ◽

Androgen Deprivation ◽

Rna Seq ◽

Genome Wide ◽

Wide Range ◽

Castrate Resistant

88 Background: Although androgen deprivation therapy initially decreases PC tumor burden, resistance to further androgen receptor (AR)-directed treatments or chemotherapy is inevitable once CRPC is established. We postulated that the stress of ADT triggers widespread alterations in expression that renders a metastable physiologic state conditioned by epigenetic changes that might be initially reversible by targeting non-androgen pathways. We conducted a pilot study to explore genome-wide expression alterations in PC foci surviving 3 months ADT (eADT). Methods: mRNA from 7 frozen microdissected PC foci and normal counterparts (NC) were processed for RNA-seq. RNA-seq changes in eADT specimens were compared first with NC and the untreated PC in the TCGA PRAD (TCGA) database to castrate resistant (mCRPC) specimens in the dbGAP study phs000915.v1.p1database. The raw data (fastq files) was quantified using kallisto, normalized by TMM using R package edgeR, batch effects corrected using R package SVA. Analysis of differential gene expression by R package sleuth. Pathway and gene set by GSEA, GAGE/pathview packages for Gene Ontology (GO) and KEGG. Results: TMPRSS2-ERG+, 5/7. Highest DEG in eADT vs. TCGA vs mCRPC were non-coding RNA’s. Among 17431 differentially regulated paths; GSEA of eADT vs TCGA or mCRPC: 341 (1.95%) and 1366 (7.84%) up- vs 46 (0.26%) and 59 (0.34%) down-regulated. KEGG paths, eADT vs. TCGA or mCRPC, 11 and 53 up vs. 2 and 3 down- respectively. Highly down- path in eADT vs TCGA (log q < 10-17) was ribosomal vs. cell cycle and DNA replication in mCRPC. Six paths significantly up- in eADT vs TCGA or mCRPC: Wnt, adherence junction, steroid biosynthesis, unsaturated fatty acids, citrate cycle, ErbB. Calcium, MAPK, insulin, GnRH and Hedgehog were also up- in eADT vs mCRPC. AR full-length was marginally higher in eADT than TCGA and lower than mCRPC, no differences in gene targets. Conclusions: This pilot data shows that ADT triggers a wide range of gene expression alterations that support PC cell survival and may be vulnerable to therapeutic targeting in addition to the androgen pathway. Validation of these findings is planned in a larger set of samples from the same bank.

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