Abstract PO-117: CHD1-loss promotes tumor heterogeneity and therapy resistance in prostate cancer

Abstract

Abstract Targeted therapies for driver oncogenes have transformed the management of many cancers but the magnitude and duration of response remains variable. One potential explanation for the various response is the presence of additional genomic alterations which modify the degree of dependence on the targeted driver mutation. Metastatic castration resistant prostate cancer (mCRPC) serves as an example, where the target is the androgen receptor (AR). Compared to primary disease, mCRPC is characterized by extensive heterogeneity at both genomic and transcriptional levels, including genomic copy number alterations (CNAs), which are presumed to contribute to the resistance to AR targeted therapies. To gain functional insight into the genes impacted by the copy number alterations in mCRPC, we screened 730 genes often deleted in prostate cancer for CNAs that confer in vivo resistance and identified the chromodomain helicase DNA-binding protein 1 (CHD1) as a top candidate modifying resistance, a finding supported by patient data showing that CHD1 expression is inversely correlated with clinical benefit from therapy. Depletion of CHD1 in multiple human prostate cancer cell lines confers significant resistance to enzalutamide both in vitro and in vivo. Furthermore, we observed global changes in open and closed chromatin after the depletion of CHD1, indicative of an altered chromatin state, with associated changes in gene expression. Integrative analysis of ATAC-seq and RNA-seq, combining with CRISPR-based screen, identified four heterogenous resistance drivers (GR, BRN2, NR2F1, TBX2), which are elevated in different independently derived, enzalutamide-resistant, CHD1-deleted subclones. Importantly, significantly increased transcriptional heterogeneity was observed in these CHD1-depleted resistant tumors and in the tumor samples from a large mCRPC patients’ cohort. Finally, GR inhibition restored the enzalutamide sensitiivty in resistant tumors with elevated GR signaling. These results suggest CHD1-loss, through global effects on chromatin, establishes a state of plasticity that accelerates the development of AR targeted therapy resistance through activation of heterogeneous downstream effectors, which mediated the transition away from luminal lineage identity and AR dependency. This model not only provides an innovative explanation for the significantly increased transcriptional heterogeneity observed in mCRPC patients, but also suggests that proper clinical interventions targeting these heterogenous resistance drivers may be a novel avenue to prevent or even reverse resistance towards AR targeted therapies. Citation Format: Zeda Zhang, Chuanli Zhou, Xiaoling Li, Charles Sawyers, Ping Mu. CHD1-loss promotes tumor heterogeneity and therapy resistance in prostate cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-117.