PARP inhibition suppresses GR-MYCN-CDK5-RB1-E2F1 signaling and neuroendocrine differentiation in castration-resistant prostate cancer Journal Article
| Authors: | Liu, B.; Li, L.; Yang, G.; Geng, C.; Luo, Y.; Wu, W.; Manyam, G. C.; Korentzelos, D.; Park, S.; Tang, Z.; Wu, C.; Dong, Z.; Sigouros, M.; Sboner, A.; Beltran, H.; Chen, Y.; Corn, P. G.; Tetzlaff, M. T.; Troncoso, P.; Broom, B.; Thompson, T. C. |
| Article Title: | PARP inhibition suppresses GR-MYCN-CDK5-RB1-E2F1 signaling and neuroendocrine differentiation in castration-resistant prostate cancer |
| 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 in vitro and in NEPC tumors in vivo. 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 OLAþDINA combination therapy in NEPC xenograft models. © 2019 American Association for Cancer Research. |
| Keywords: | signal transduction; controlled study; protein phosphorylation; unclassified drug; human cell; nonhuman; protein function; mouse; reverse transcription polymerase chain reaction; gene expression; tumor differentiation; animal experiment; animal model; small interfering rna; dexamethasone; in vivo study; cell differentiation; in vitro study; tumor xenograft; rna; genetic transfection; drug mechanism; chromatin immunoprecipitation; immunoblotting; prostate adenocarcinoma; upregulation; retinoblastoma protein; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; transcription factor e2f1; olaparib; rna sequence; glucocorticoid receptor; castration resistant prostate cancer; retinoblastoma protein 1; neuroendocrine differentiation; cyclin dependent kinase 5; enzalutamide; human; male; priority journal; article; prostate epithelium cell; dinaciclib; talazoparib; n myc proto oncogene protein; lncap c4-2b cell line |
| Journal Title: | Clinical Cancer Research |
| Volume: | 25 |
| Issue: | 22 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2019-11-01 |
| Start Page: | 6839 |
| End Page: | 6851 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-19-0317 |
| PUBMED: | 31439587 |
| PROVIDER: | scopus |
| PMCID: | PMC6858969 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 December 2019 -- Source: Scopus |
