Abstract B010: Therapeutic targeting of PRC1 complexes to induce neuroblastoma differentiation

Abstract

Pediatric cancers are frequently driven by genomic alterations that result in aberrant transcription factor activity and impaired differentiation during tissue development. Normal development requires precise patterns of gene expression programs, which are regulated by epigenetic-modifying complexes. Epigenetic regulation of transcription is critical for maintaining a de-differentiated oncogenic state in cancers, particularly pediatric, and targeting disease-relevant epigenetic regulators can exhibit antitumor activity. To identify protein complex-level dependencies required for neuroblastoma, a pediatric cancer of the developing peripheral nervous system, we curated a list of protein complexes using the CORUM database and mined the Dependency Map (DepMap) using single sample gene set enrichment analysis. This analysis identified the non-canonical PRC1.1 complex, which represses transcriptional activity through ubiquitination of histone 2A, lysine 119 (H2AK119Ub), is a selectively enriched dependency in neuroblastoma. Knockout of several PRC1.1 subunits (i.e. PCGF1, BCOR, and KDM2B) reduced neuroblastoma growth, arrested the cell cycle, and induced a neuronal differentiation program. While no known direct inhibitors of non-canonical PRC1.1 exist, co-dependency analysis of PRC1.1 subunits against all other genes in DepMap identified that the deubiquitinase USP7 strongly correlated with PRC1.1 dependency. Treatment with XL177A, a small molecule inhibitor of USP7, significantly reduced neuroblastoma growth in both cellular and animal models. Integrated RNA- and ChIP-sequencing showed that both PRC1.1 knockout and USP7 inhibition resulted in highly correlated transcriptional alterations and reduced H2AK119Ub deposition on chromatin, suggesting that USP7 inhibition reduced neuroblastoma growth through a PRC1.1-dependent mechanism. Mechanistically, global proteomics and ubiquitinomics revealed that USP7 inhibition disrupted non-canonical PRC1 complex assembly, resulting in destabilization of PRC1.1 and subsequent proteolysis. Our findings expand our understanding of the chromatin complexes required to maintain a de-differentiated state in neuroblastoma and suggest the therapeutic potential for USP7 inhibitors in the treatment of neuroblastoma. Nathaniel W. Mabe. Therapeutic targeting of PRC1 complexes to induce neuroblastoma differentiation [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B010.