In this study we addressed the underlying mechanisms for the association between enzalutamide treatment and NEPC, and the critical involvement of MYCN, and loss of RB1 function in 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 utilized a novel prostate cancer PDX treatment model, prostatic adenocarcinoma and NEPC cell lines, an NEPC organoid line, and NEPC xenograft models to address the mechanistic basis of enzalutamide (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 patient-derived xenograft (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- 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 neuroendocrine prostate cancer (NEPC) cells in vitro and in NEPC tumors in vivo.
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.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2019 Aug 22 [Epub ahead of print]
Bo Liu, Likun Li, Guang Yang, Chuandong Geng, Yong Luo, Wenhui Wu, Ganiraju Manyam, Dimitrios Korentzelos, Sanghee Park, Zhe Tang, Cheng Wu, Zhenyang Dong, Michael Sigouros, Andrea Sboner, Himisha Beltran, Yu Chen, Paul Corn, Michael T Tetzlaff, Patricia Troncoso, Bradley M Broom, Timothy C Thompson
Department of oncology, Tongji Hospital., Department of Genitourinary Medical Oncology – Research, The University of Texas MD Anderson Cancer Center., Department of Biostatistics, The University of Texas MD Anderson Cancer Center., Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center., Department of Genitourinary Medical Oncology – Research, UT M. D. Anderson Center., Department of Genitourinary Medical ONcology, UT M. D. Anderson Cancer Center., Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine., Pathology and Laboratory Medicine, Weill Cornell Medicine., Medical Oncology, Dana-Farber Cancer Institute., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center., GU Medical Oncology, Unit 1374, MD Anderson., Pathology, University of Texas MD Anderson Cancer Center., Pathology, The University of Texas MD Anderson Cancer Center., Bioinformatics & Computational Biology, University of Texas MD Anderson Cancer Center., Department of Genitourinary Medical Oncology – Research, The University of Texas MD Anderson Cancer Center .