ATRT-04. TARGETING THE COREST COMPLEX HELPS REPROGRAM AT/RT’S ABNORMAL EPIGENETIC LANDSCAPE TOWARD A DIFFERENTIATION PHENOTYPE

Abstract

Abstract Atypical teratoid/rhabdoid tumors (AT/RT) are deadly infantile brain tumors. Their aggressive phenotype results from a single recurring biallelic loss-of-function mutation in genes encoding components of the SWI/SNF chromatin-remodeling complex - mainly SMARCB1 and SMARCA4 in remaining tumors. Residual SWI/SNF activity continues to inhibit EZH2 methyltransferase except at promoter regions colocalized to REST, which associates with neuronal differentiation and tumor suppressor genes. At these sites, EZH2 increases repressive H3K27me3 marks, helping maintain AT/RT in a stem cell-like state, and driving its aggressive growth and therapy resistance. We study the consequences of disrupting SWI/SNF inhibition at sites of EZH2/REST co-localization to target AT/RT precisely. The repressive action of REST is carried out mainly by the CoREST complex, consisting of LSD1, HDAC1/2 and RCOR. Lentiviral knockdown of RCOR2 reversed AT/RT’s stem cell-like state and induced differentiation along the glial and neuronal lineage. A decrease in the H3K27Me3 further confirmed the absence of COREST complex assembly at these sites. We used a bifunctional LSD1 and HDAC1/2 inhibitor, Corin, to pharmacologically target the CoREST complex in AT/RT cells. Corin also induced neuronal differentiation in AT/RT with increased expression of neuronal differentiation markers and decreased expression of stem cell markers. Further, Corin reduced AT/RT cell viability and proliferation (p<0.05) and increased apoptosis (p<0.05). In mice bearing orthotopic CHLA06 tumors, convection-enhanced delivery of a single dose of Corin increased H3K27ac, demonstrating that Corin engaged its target in vivo and induced apoptosis (western blot, cPARP). These studies demonstrate that targeting the CoREST complex disrupts AT/RT epigenetic abnormalities, reversing their stem cell-like state, slowing tumor cell growth, and inducing apoptosis. Targeting the CoREST complex with Corin is a promising new strategy that may translate into the clinical setting to help improve AT/RT’s dismal survival.