Abstract 1807: miRNA alterations associated with transition of advanced castration-resistant prostate cancer to neuroendocrine prostate cancer

Neuroendocrine prostate cancer (NEPC) is an aggressive variant of advanced prostate cancer (PCa) present in ~30% of metastatic castration-resistant tumors, often emerging as a result of AR-targeted therapies such as enzalutamide. NEPC arises via a reversible trans-differentiation process, referred to as neuroendocrine differentiation (NED), wherein cells undergo a lineage switch to an androgen-independent state and exhibit neuroendocrine (NE) features, such as expression of neuronal markers. Clinically, NEPC manifests as the presence of visceral metastatic disease, low serum PSA levels relative to disease burden and limited response to AR signaling inhibitors. The molecular mechanistic basis of NEPC is poorly understood contributing to the lack of effective therapies and robust molecular markers for its diagnosis and prognosis. A few studies have characterized NEPC tumors at a molecular level and identified key genomic events promoting NE states including frequent TMPRSS2-ERG rearrangements, RB1/TP53 loss, amplification/overexpression of Aurora kinase A, N-myc and EZH2. Though these studies have characterized the key genomic lesions associated with NEPC, the role of microRNAs (miRNAs) in NED have not been systematically explored. Considering the important regulatory role of miRNAs, this is a critical drawback contributing to a poor understanding of molecular basis of NEPC. We hypothesize that this switch is associated with significant alterations to the miRNAome, that in turn, drives switching of cellular gene expression patterns towards NE states and in this study, we sought to define the miRNA alterations associated with progression of advanced castration-resistant prostate cancer (CRPC) to androgen-independent neuroendocrine state. We tested our hypothesis by assessing miRNA alterations associated with transition from CRPC with adenocarcinoma features to that with NE features by performing small RNA-NGS in patient samples and in cellular models. Our data suggests that transition to NE states is associated with significant miRNA alterations such as downregulation of miRNAs belonging to miR-379-410 cluster (located on chromosome 14q32) and miR-17/92 cluster (located on chromosome 13q31). Further, our analyses identified that NEPC is associated with upregulation of transcription factors (TFs) SP1, SP4 and POU domain TFs such as POU2F1 (Oct1), POU3F3 (BRN3), POU3F4 (BRN4), in addition to already reported upregulation of POU3F2 (BRN2). We found that miRNAs belonging to miR-17-92 and 379-410 clusters potentially regulate expression of POU domain TFs. To conclude downregulation of these miRNAs upon NED induction, may lead to upregulation of key NE-associated TFs, that in turn, drives the expression of neuronal genes associated with neuroendocrine differentiation states in prostate cancer. Citation Format: Divya Bhagirath, Thao Yang, Laura Tabatabai, Shahana Majid, Rajvir Dahiya, Yuichiro Tanaka, Sharanjot Saini. miRNA alterations associated with transition of advanced castration-resistant prostate cancer to neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1807.