Abstract 1580: Combined neuroendocrine differentiation and androgen receptor hyperactivity in MAP37 and CHD1 null prostate cancer

Abstract

Abstract We recently functionally validated a clinically aggressive subtype of prostate cancer characterized by dual deletion of MAP3K7 and CHD1. This subtype accounts for up to 25% of prostate cancer deaths. Androgen signaling is a critical component of prostate tumorigenesis and disease progression, which is exploited in treatment of prostate cancer with androgen deprivation and anti-androgen therapies. Neuroendocrine differentiation is thought to provide a selective growth advantage of prostate cancer in androgen-depleted conditions such as surgical or chemical castration. REST is a transcriptional repressor of neuronal gene expression and has been implicated in neuroendocrine differentiation of prostate cancer. The impact of combined MAP3K7 and CHD1 loss on androgen signaling and neuroendocrine differentiation has not been determined. Here, we demonstrate that dual loss of MAP3K7 and CHD1 simultaneously stimulates enhanced androgen signaling and enhanced neuronal differentiation correlated with enhanced growth in both androgen-depleted and androgen-replete conditions. These changes occur via increased androgen receptor chromatin binding, loss of CHD1 chromatin binding, loss of REST expression, and reduced chromatin binding by REST. Suppression of CHD1 and MAP3K7 attenuates the antiproliferative activity of the anti-androgen Enzalutamide. Furthermore, we translate these findings to clinical samples and show that decreased expression of CHD1, MAP3K7, and REST is associated with previous therapeutic intervention, castrate-resistant disease, and progression to a neuroendocrine phenotype. Overall, patients with low expression of all three have poorer disease-free survival. Together these data support the lineage plasticity of prostate tumors with loss of CHD1 and MAP3K7 exhibiting both androgen-dependent and -independent phenotypes leading to poor clinical outcome, which poses challenges to conventional therapeutic approaches. Citation Format: Leah C. Rider, Lindsey U. Rodrigues, Anis Karimpour-Fard, Lina Romero, Claire Gillette, James C. Costello, Scott D. Cramer. Combined neuroendocrine differentiation and androgen receptor hyperactivity in MAP37 and CHD1 null prostate cancer [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 1580. doi:10.1158/1538-7445.AM2017-1580