Abstract 2170: Rb1 suppresses prostate cancer metastasis and lineage plasticity underlying castration resistance
Authors: Ku Sheng-Yu , Rosario Spencer , Wang Yanqing , Mu Ping , Seshadri Mukund , Goodrich Zachary , Goodrich Maxwell , Labbé David P. , Gomez Eduardo Cortez , Wang Jianmin , Long Henry W. , Xu Bo , Brown Myles , Loda Massimo , Sawyers Charles L. , Ellis Leigh , Goodrich David G. 
Published: July 2017

Androgen deprivation therapy (ADT) is an effective treatment for metastatic prostate cancer (mPCa), but patients eventually relapse with ADT resistant disease. Well-characterized mechanisms of ADT resistance include AR amplification, intra-tumoral androgen synthesis, AR splice variants, and growth receptor bypass. All of these mechanisms function to maintain sufficient AR signaling for tumor growth and survival. Improved ADT like abiraterone acetate (AA) and enzalutamide (Enza) were developed to combat such resistance mechanisms associated with alterations in androgen receptor or androgen metabolism. While AA and Enza extend survival, clinical benefits are short-lived. A new form of resistance is increasingly appreciated in patients relapsing from AA or Enza, histologic transformation of prostate adenocarcinoma (PADC) to neuroendocrine prostate cancer (NEPC) variants. NEPC is lethal and the survival time is less than a year as effective targeted therapy is unavailable. NEPC typically exhibits reduced AR expression, increased expression of neuroendocrine markers, and visceral metastasis in the absence of rising PSA. Of note, NEPC possesses the similar genome rearrangements with adjacent PADC cells, indicating they share clonal origin. Thus, NEPC may arise by histologic transformation of PADC. Underlying mechanisms of histologic transformation are not understood and experimental models are limited, hindering development of effective remedies. RB1 loss is common in NEPC, but rare in PADC; genetic profiling shows human NEPC exhibit elevated levels of several epigenetic modifiers. We hypothesize that transdifferentiation from PADC to NEPC in the context of RB1 loss is due to epigenetic alterations and can be reversed or blocked by epigenetic targeted therapies. We established several genetically engineered mouse models (GEMMs) to test the role of Rb1, and we find Rb1 loss causes metastatic progression of PADC initiated by Pten deficiency. This Rb1/Pten deficient (DKO) PADC exhibits expression markers for both PADC and NEPC as seen in human patients. Yet, these tumors are sensitive to ADT but relapse with low AR expression and acquired Trp53 mutations. RNA profiling demonstrates the phenotype of DKO tumors is similar to human NEPC. Both human and mouse NEPC is accompanied by increased expression of epigenetic reprogramming factors like Sox2 and Ezh2. Clinically relevant Ezh2 inhibitors GSK126 and EPZ6438 can restore Enza sensitivity by reversing neuroendocrine transformation. This finding has been genetically validated using short-hairpin RNA(shRNA) in vitro. These results uncover genetic mutations driving prostate cancer lineage plasticity and suggest an epigenetic approach for extending the clinical benefits of ADT.

Citation Format: Sheng-Yu Ku, Spencer Rosario, Yanqing Wang, Ping Mu, Mukund Seshadri, Zachary Goodrich, Maxwell Goodrich, David P. Labbé, Eduardo Cortez Gomez, Jianmin Wang, Henry W. Long, Bo Xu, Myles Brown, Massimo Loda, Charles L. Sawyers, Leigh Ellis, David G. Goodrich. Rb1 suppresses prostate cancer metastasis and lineage plasticity underlying castration resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2170. doi:10.1158/1538-7445.AM2017-2170