PARP Inhibition Suppresses GR–MYCN–CDK5–RB1–E2F1 Signaling and Neuroendocrine Differentiation in Castration-Resistant Prostate Cancer

• Published in: Clinical cancer research Vol. 25; no. 22; pp. 6839 - 6851
• Main Authors: Liu, Bo, Li, Likun, Yang, Guang, Geng, Chuandong, Luo, Yong, Wu, Wenhui, Manyam, Ganiraju C., Korentzelos, Dimitrios, Park, Sanghee, Tang, Zhe, Wu, Cheng, Dong, Zhenyang, Sigouros, Michael, Sboner, Andrea, Beltran, Himisha, Chen, Yu, Corn, Paul G., Tetzlaff, Michael T., Troncoso, Patricia, Broom, Bradley, Thompson, Timothy C.
• Format: Journal Article
• Language: English
• Published: United States 15.11.2019
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bridged Bicyclo Compounds, Heterocyclic - administration & dosage; Cell Line, Tumor; Cyclin-Dependent Kinase 5 - genetics; Cyclin-Dependent Kinase 5 - metabolism; E2F1 Transcription Factor - genetics; E2F1 Transcription Factor - metabolism; Gene Expression Regulation, Neoplastic - drug effects; Humans; Male; Mice, Nude; N-Myc Proto-Oncogene Protein - genetics; N-Myc Proto-Oncogene Protein - metabolism; Neuroendocrine Tumors - drug therapy; Neuroendocrine Tumors - genetics; Neuroendocrine Tumors - metabolism; Phenylthiohydantoin - administration & dosage; Phenylthiohydantoin - analogs & derivatives; Phthalazines - administration & dosage; Piperazines - administration & dosage; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - metabolism; Proteins - genetics; Proteins - metabolism; Pyridinium Compounds - administration & dosage; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; Retinoblastoma Binding Proteins - genetics; Retinoblastoma Binding Proteins - metabolism; Signal Transduction - drug effects; Signal Transduction - genetics; Treatment Outcome; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Xenograft Model Antitumor Assays - methods
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-19-0317

In this study, we addressed the underlying mechanisms for the association between enzalutamide (ENZ) treatment and neuroendocrine prostate cancer (NEPC), and the critical involvement of MYCN, and loss of RB1 function in neuroendocrine differentiation (NED) of prostatic epithelial cells, and the development of NEPC. We further sought to determine whether PARP inhibition could suppress NEPC, and to identify molecular determinants of this therapeutic activity. We used a novel prostate cancer patient-derived xenograft (PDX) treatment model, prostatic adenocarcinoma and NEPC cell lines, an NEPC organoid line, and NEPC xenograft models to address the mechanistic basis of ENZ-induced NED, and to analyze suppression of NED and NEPC growth by PARP inhibition. We identified an ENZ treatment-associated glucocorticoid receptor (GR)-MYCN-CDK5-RB1-E2F1 signaling pathway that drives NED in prostatic adenocarcinoma PDX and cell line models. Mechanistically, long-term ENZ treatment transcriptionally upregulates signaling of the GR-MYCN axis, leading to CDK5R1 and CDK5R2 upregulation, Rb1 phosphorylation, and N-Myc-mediated and E2F1-mediated NED gene expression. Importantly, olaparib (OLA) or talazoparib (TALA) suppressed these activities, and the combination of OLA and dinaciclib (DINA), an inhibitor of CDK2 and CDK5, which also inhibits Rb1 phosphorylation, suppressed NED and significantly improved therapeutic efficiency in NEPC cells and in NEPC tumors . The results of our study indicate an important role of GR-MYCN-CDK5R1/2-RB1-NED signaling in ENZ-induced and PARP inhibitor-suppressed NEPC. We also demonstrated efficacy for OLA+DINA combination therapy in NEPC xenograft models.