Abstract 1404: MicroRNA-mediated induction of neuroendocrine differentiation states in metastatic castration-resistant prostate cancer
Authors: Divya Bhagirath, Michael Liston, Byron Lui, Dat My To, Thao Ly Yang, Laura Z. Tabatabai, Nikhil Patel, Roni Bollag, Adam Olshen, Sharanjot Saini
Journal: Cancer Research (2020)

Abstract While the widespread use of androgen receptor pathway inhibitors (APIs) such as enzalutamide has led to transformative impact in the management of metastatic castration-resistant prostate cancer (CRPC) patients, resistance is near-universal leading to significantly increased incidences of highly aggressive, therapy-induced neuroendocrine differentiation (NED). It has been realized that therapy-induced NED represents a continuum of treatment-induced changes at phenotypic and molecular level that involves a series of alterations at genetic, epigenetic, post-transcriptional, post-translational levels and changes in microenvironment. Though several recent studies identified key genomic and epigenomic alterations driving therapy-induced NED, the molecular pathogenesis is still not completely understood contributing to late diagnosis of the disease, poor prognosis and lack of effective therapies. The focused objective of our study was to systematically investigate the key microRNA (miRNAs) alterations that drive therapy-induced NED in PCa. We hypothesized that this lineage switch is associated with significant alterations to the miRNAome, that in turn, drives change in cellular gene expression patterns towards NE states. We tested our hypothesis by performing small RNA-NGS in a clinical cohort of patient samples, patient-derived xenograft and cellular models. We identify for the first time that a characteristic set of miRNA alterations promote plasticity of prostate tumors to NE states. Importantly, we identify downregulation of miR-363 as a prominent molecular alteration underlying PCa NED. To examine the functional role of miR-363, we knocked down its expression in CRPC cell lines C42B and LNCaP followed by functional assays. Decreased miR-363 expression resulted in increased clonogenicity potential and invasiveness of PCa cell lines as compared to control suggesting that miR-363 loss contributes to increased aggressiveness. Importantly, we found that miR-363 directly represses Aurora kinase A (AURKA), a prototypical kinase frequently amplified in NED. Correlation analyses in TCGA database of prostate adenocarcinomas (n=494) showed a significant inverse correlation between miR-363 expression and AURKA mRNA levels. In conclusion, our study identifies crucial molecular determinants of NED with potential clinical and transformative potential. Since AURKA inhibition is currently being examined as a therapeutic modality for NEPC, we propose augmentation of miR-363 levels to repress AURKA as a novel treatment option for therapy-induced NEPC. Citation Format: Divya Bhagirath, Michael Liston, Byron Lui, Dat My To, Thao Ly Yang, Laura Z. Tabatabai, Nikhil Patel, Roni Bollag, Adam Olshen, Sharanjot Saini. MicroRNA-mediated induction of neuroendocrine differentiation states in metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1404.