Abstract 3016: Ezh2 is a dose-dependent mediator of prostate cancer aggressiveness and lineage transformation
Authors: Wadosky Kristine M. , Wang Yanqing , Ellis Leigh , Goodrich David W. 
Published: August 2018

Resistance to therapies for metastatic prostate cancer (PCa) causes patients to rapidly succumb to their disease, especially when resistance is associated with development of aggressive variant PCa. These PCa variants are found in 20-30% of patient autopsies relapsing from androgen deprivation therapy (ADT) and often lack androgen receptor (AR), aberrantly express alternative lineage markers, and have altered histology and clinical course. Of these PCa variants, neuroendocrine prostate cancer (NEPC) has been the most well-studied. Our recently published data show that Rb1 loss promotes NEPC transformation in the mouse and induces pervasive changes in gene expression characteristic of human NEPC. These changes include increased expression of histone methyltransferase Ezh2, a known PCa oncogene. In addition, treatment with Ezh2 inhibitors restores AR expression and ADT sensitivity in Rb1-deficient PCa. We hypothesize that Ezh2 is a driver of NEPC transformation in Rb1-deficient PCa. To test this hypothesis, we generated a new genetically engineered mouse model (GEMM) of Rb1-deficient PCa that also lacks Ezh2. Preliminary data suggest that overall survival of PBCre4:Ptenf/f:Rb1f/f:Ezh2f/+ (DKOE/+) mice with loss of one Ezh2 allele is increased compared to PBCre4:Ptenf/f:Rb1f/f (DKO). In prostate tumors from DKOE/+ mice, individual glands are apparent, characteristic of adenocarcinoma. Immunohistochemistry shows that expression of luminal markers, including AR, CK8, and CK18, are increased in DKOE/+ compared to DKO. NEPC markers synaptophysin and chromagranin A are decreased in DKOE/+ compared to DKO, suggesting that loss of one Ezh2 allele slows neuroendocrine transformation. To our surprise, overall survival of PBCre4:Ptenf/f:Rb1f/f:Ezh2f/f (DKOE/E) was decreased compared to DKO. Histological analysis of end-stage primary tumors from DKOE/E mice indicate they develop high grade lesions containing sheets of cells with minimal gland formation. These mice develop hemorrhagic ascites and metastases to the liver, lung, kidney, bone, thymus, and lymph node. AR expression in DKOE/E is decreased compared to both DKO and DKOE/+. When organoids were established from DKO, DKOE/+, and DKOE/E end-stage tumors, preliminary analysis suggest that DKOE/E have greater organoid renewal capability. Altogether, initial data from our new GEMMs show that loss of one allele of Ezh2 in DKOE/+ inhibits development of lethal NEPC transformation in Rb1-deficient PCa. Whereas, complete loss of Ezh2 in the context of Rb1-deficiency makes disease more aggressive. These data suggest that Ezh2's effect on PCa progression in the absence of Rb1 is dose-dependent. Future work is required to investigate of the exact mechanism of Ezh2's contribution to PCa aggressiveness and NEPC transformation.

Citation Format: Kristine M. Wadosky, Yanqing Wang, Leigh Ellis, David W. Goodrich. Ezh2 is a dose-dependent mediator of prostate cancer aggressiveness and lineage transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3016.