Molecular Characterization of Neuroendocrine Prostate Cancer and Identification of New Drug Targets

Abstract

Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer that most commonly evolves from preexisting prostate adenocarcinoma (PCA). Using Next Generation RNA-sequencing and oligonucleotide arrays, we profiled 7 NEPC, 30 PCA, and 5 benign prostate tissue (BEN), and validated findings on tumors from a large cohort of patients (37 NEPC, 169 PCA, 22 BEN) using IHC and FISH. We discovered significant overexpression and gene amplification of AURKA and MYCN in 40% of NEPC and 5% of PCA, respectively, and evidence that that they cooperate to induce a neuroendocrine phenotype in prostate cells. There was dramatic and enhanced sensitivity of NEPC (and MYCN overexpressing PCA) to Aurora kinase inhibitor therapy both in vitro and in vivo, with complete suppression of neuroendocrine marker expression following treatment. We propose that alterations in Aurora kinase A and N-myc are involved in the development of NEPC, and future clinical trials will help determine from the efficacy of Aurora kinase inhibitor therapy.

Loss of PKCδ Induces Prostate Cancer Resistance to Paclitaxel through Activation of Wnt/β-Catenin Pathway and Mcl-1 Accumulation

“…We are the first to show a strong correlation between high active b-catenin immunohistochemical expression and high Gleason score prostate tumors. Many studies have linked overexpression of AurKA with progression and malignant phenotype of prostate cancers (41)(42)(43)(44), although there are controversial results with respect to its correlation with the Gleason score (45,46). We observed a significant correlation between high expression of AurKA and high Gleason score tumors.…”

The N-myc Oncogene: Maximizing its Targets, Regulation, and Therapeutic Potential

“…Similarly, short hairpin RNA (shRNA)-mediated silencing of N-myc in neuroblastoma cells has identified a 157 target-gene panel including those involved cell cycle, DNA repair, and neuronal differentiation genes; this panel has been associated with poor prognosis in patients with neuroblastoma. More recently, a similar set of N-myc-targeted genes has been observed in neuroendocrine prostate cancer, with upregulation of cell cycle and neuroendocrine type genes (35,56). In prostate cancer, Nmyc binds neuroendocrine and androgen-regulated gene promoters, suggesting direct involvement in neuroendocrine transformation.…”

“…N-myc amplification rarely occurs in other lung cancer histologies. N-myc amplification also occurs in approximately 40% of neuroendocrine/small-cell prostate cancers, is commonly seen concurrently with amplification of the aurora kinase A gene (AURKA), and associated with poor prognosis (35,36). In both small-cell lung and prostate cancers, N-myc amplification may occur early before the development of metastasis.…”

“…AURKA is also frequently overexpressed and amplified in N-myc-amplified tumors such as neuroblastoma and neuroendocrine prostate cancer (35,69), and cooperates with N-myc to promote tumor proliferation and oncogenic activity. N-myc-amplified neuroblastoma cells depend on high levels of AURKA expression for maintaining N-Myc function (69).…”

Construction of a set of novel and robust gene expression signatures predicting prostate cancer recurrence

“…VAV2 is a coactivator of androgen receptor (AR) and sustains AR signaling under androgen deprivation therapy (ADT) (Magani et al ., 2017); it also promotes angiogenesis and metastasis (Barrio‐Real and Kazanietz, 2012). AURKA plays a critical role in mitosis (Dominguez‐Brauer et al ., 2015; Plotnikova et al ., 2015) and promotes the development of neuroendocrine PC under ADT (Beltran et al ., 2011; Mosquera et al ., 2013). DNMT3B may regulate epigenetic events to facilitate CRPC development (Hoffmann et al ., 2007).…”