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Expression profiling by high throughput sequencing of tumors derived from human prostate epithelial cells transformed with the oncogenes N-Myc and myrAKT1.

ABSTRACT: MYCN amplification and overexpression are common in neuroendocrine prostate cancer (NEPC). However, the impact of aberrant N-Myc expression in prostate tumorigenesis and the cellular origin of NEPC have not been established. We define N-Myc and activated AKT1 as oncogenic components sufficient to transform human prostate epithelial cells to prostate adenocarcinoma and NEPC including the small cell prostate carcinoma (SCPC) variant with phenotypic and molecular features of aggressive, late-stage human disease. We directly show that prostate adenocarcinoma and NEPC can both arise from a common epithelial clone. Further, N-Myc is required for tumor maintenance and destabilization of N-Myc through Aurora A kinase inhibition reduces tumor burden. Our findings establish N-Myc as a driver of NEPC and a target for therapeutic intervention. Expression profiling by high throughput sequencing of experimentally generated human tumors with mixed NEPC and prostate adenocarcinoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE77624 | GEO | 2016/02/06

SECONDARY ACCESSION(S): PRJNA311066

REPOSITORIES: GEO

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Project description:Histone deacetylation is crucial for the regulation of chromatin structure, gene transcription and the epigenetic state of the cell. With the emergence of the neuroendocrine (NE) phenotype in castration-resistant prostate cancer (CRPC), we hypothesized that the inhibition of HDAC1/2 would disrupt the epigenetic events involved in the conversion of prostate adenocarcinoma to a NE prostate cancer (NEPC) phenotype. Additionally, monotherapies tend to have limited efficacy in cancer treatment and combination treatments show more promise. Since the PI3K/AKT/mTOR pathway is a well-established tumor growth-promoting pathway and a promising target in CRPC and NEPC, we investigated the tumor suppressing activities of fimepinostat, a dual HDAC and PI3K inhibitor, on both prostate adenocarcinoma and NEPC. We evaluated multiple cell lines and patient-derived xenograft (PDX) models of prostate adenocarcinoma and NEPC to determine the roles of HDAC1/2 and AKT inhibition, both individually and in combination, in suppressing CRPC and NEPC tumor growth in vitro and in vivo. HDAC1/2 inhibition in combination with PI3K/AKT inhibition was more efficacious than targeting each pathway alone, induced growth inhibitory effects (in some cases synergistic) through cell cycle inhibition and apoptosis across an array of prostate adenocarcinoma and NEPC patient-derived xenografts (PDX) and cell lines in vitro and in vivo. Molecular profiling revealed on-target effects of combined HDAC1/2 and PI3K/AKT inhibition as well as a common downregulation of Myc, E2F, DNA repair, and G2M checkpoint targets, independent of prostate cancer phenotype. Fimepinostat therapy was also associated with the suppression of lineage transcription factor expression including androgen receptor (AR) in prostate adenocarcinoma and Achaete-scute homolog 1 (ASCL1) in NEPC. Our findings demonstrate that dual HDAC1/2 and PI3K/AKT pathway inhibition leads to robust tumor growth inhibition in both adenocarcinoma and NEPC, suggesting that fimepinostat may represent a novel therapeutic for both prostate adenocarcinoma and NEPC phenotypes of CRPC.

Project description:Introduction: Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer, exhibiting rapid progression and is unresponsive to hormone therapy. Reliable prognostic assays and more effective treatments are critically required. However, the research of NEPC has been hampered by a lack of clinically relevant in vivo models. Recently, we successfully developed a first-in-field patient tissue-derived xenograft model of complete neuroendocrine transdifferentiation from prostate adenocarcinoma. By comparing gene expression profiles of the parental adenocarcinoma line (LTL331) and the NEPC subline (LTL331R), we identified DEK, a gene not previously reported in prostate cancer, as a potential biomarker and target for NEPC. Methods: DEK protein expression in patient tissue-derived xenograft models and clinical samples was assessed by immunohistochemistry. The function of DEK was determined by siRNA-induced reduction of DEK expression in PC-3 cells, a cell line with NEPC characteristics, followed by functional assays and gene expression profiling analysis. Results: Elevated DEK protein expression was observed in all clinical NEPC cases, which is distinct from their benign counterparts (0%), hormonal naïve prostate cancer (2.45%) and castration resistant prostate cancer (29.55%). Increased DEK expression is an independent clinical risk factor and is associated with shorter disease free survival in hormonal naïve prostate cancer patients. Reduction of DEK expression in PC-3 cells led to a marked reduction in cell proliferation, cell migration and invasion. Conclusions: The results suggest that DEK may play an important role in the progression of prostate cancer, especially NEPC and provide a potential biomarker to aid risk stratification of prostate cancer and a novel therapeutic target for treating NEPC. The function of DEK was determined by siRNA-induced reduction of DEK expression in PC-3 cells, a cell line with NEPC characteristics, followed by functional assays and gene expression profiling analysis.

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Expression profiling by high throughput sequencing of tumors derived from human prostate epithelial cells transformed with the oncogenes N-Myc and myrAKT1.

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