Abstract A2-11: PLZF, a tumor suppressor genetically lost in metastatic castration resistant prostate cancer, is a mediator of resistance to androgen deprivation therapy

Abstract

Abstract Whole exome sequencing of metastatic castration-resistant prostate cancer (mCRPC) reveal that 5~7% of tumors harbor promyelocytic zinc finger protein (PLZF) homozygous deletions. PLZF is a canonical androgen-regulated tumor suppressor gene whose expression is inhibited by androgen deprivation therapy (ADT). Here, we demonstrate that knockdown of PLZF expression promotes a CRPC and enzalutamide resistant phenotype in prostate cancer cells. Reintroduction of PLZF expression is sufficient to reverse androgen-independent growth mediated by PLZF depletion. PLZF loss enhances CRPC tumor growth in a xenograft model. Bioinformatic analysis of the PLZF cistrome shows that PLZF negatively regulates multiple pathways including the MAPK pathway. Accordingly, our data support an oncogenic program activated by ADT and this acquired mechanism together with the finding of genetic loss in CRPC implicate PLZF inactivation as a mechanism promoting ADT resistance and the CRPC phenotype. Citation Format: Chen-Lin Hsieh, Ginevra Botta, Shuai Gao, Tiantian Li, Eliezer M. Van Allen, Daniel J. Treacy, Changmeng Cai, Housheng Hansen He, Christopher J. Sweeney, Myles Brown, Steven P. Balk, Peter S. Nelson, Levi A. Garraway, Philip W. Kantoff. PLZF, a tumor suppressor genetically lost in metastatic castration resistant prostate cancer, is a mediator of resistance to androgen deprivation therapy. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-11.