Title | PARP Inhibition Suppresses GR-MYCN-CDK5-RB1-E2F1 Signaling and Neuroendocrine Differentiation in Castration-Resistant Prostate Cancer. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Liu B, Li L, Yang G, Geng C, Luo Y, Wu W, Manyam GC, Korentzelos D, Park S, Tang Z, Wu C, Dong Z, Sigouros M, Sboner A, Beltran H, Chen Y, Corn PG, Tetzlaff MT, Troncoso P, Broom B, Thompson TC |
Journal | Clin Cancer Res |
Volume | 25 |
Issue | 22 |
Pagination | 6839-6851 |
Date Published | 2019 Nov 15 |
ISSN | 1557-3265 |
Keywords | Animals, Antineoplastic Combined Chemotherapy Protocols, Benzamides, Bridged Bicyclo Compounds, Heterocyclic, Cell Line, Tumor, Cyclic N-Oxides, Cyclin-Dependent Kinase 5, E2F1 Transcription Factor, Gene Expression Regulation, Neoplastic, Humans, Indolizines, Male, Mice, Nude, N-Myc Proto-Oncogene Protein, Neuroendocrine Tumors, Nitriles, Phenylthiohydantoin, Phthalazines, Piperazines, Poly(ADP-ribose) Polymerase Inhibitors, Prostatic Neoplasms, Castration-Resistant, Proteins, Pyridinium Compounds, Receptors, Glucocorticoid, Retinoblastoma Binding Proteins, Signal Transduction, Treatment Outcome, Ubiquitin-Protein Ligases, Xenograft Model Antitumor Assays |
Abstract | PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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 . CONCLUSIONS: 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. |
DOI | 10.1158/1078-0432.CCR-19-0317 |
Alternate Journal | Clin Cancer Res |
PubMed ID | 31439587 |
PubMed Central ID | PMC6858969 |
Grant List | P30 CA016672 / CA / NCI NIH HHS / United States P50 CA140388 / CA / NCI NIH HHS / United States R01 CA193837 / CA / NCI NIH HHS / United States P50 CA092629 / CA / NCI NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States R01 CA208100 / CA / NCI NIH HHS / United States U01 CA224044 / CA / NCI NIH HHS / United States |