Abstract A043: Combination Therapeutic Targeting of Chromatin Complexes in Neuroblastoma

Abstract Epigenetic dysregulation drives many pediatric tumors, including neuroblastoma, an aggressive malignancy that accounts for approximately 15% of childhood cancer deaths. Drugs targeting epigenetic regulators have emerged, with FDA approvals of tazemetostat for patients with metastatic or locally advanced epithelioid sarcoma with incomplete resection and for patients with relapsed or refractory follicular lymphoma with EZH2 mutations. More recently, the menin inhibitor revumenib was FDA approved for children and adults with relapsed/refractory KMT2A-rearranged acute myeloid leukemia. Unfortunately, these drugs are generally not curative, and resistance develops by multiple mechanisms suggesting that combination therapies are needed. Our laboratory recently identified some neuroblastomas, particularly MYCN amplified, that are dependent on the SAGA complex, a transcriptional coactivator complex that regulates gene expression by modifying histones. Knockout of TADA2B, a gene essential to the histone acetyltransferase function of SAGA, or treatment with GSK699, a selective degrader of KAT2A and KAT2B, the canonical catalytic acetyltransferases of SAGA, causes cell cycle arrest and delayed progression in xenograft models of neuroblastoma. In order to nominate combination strategies with SAGA inhibitors, we used orthogonal approaches: DepMap nearest neighbor analysis and a CRISPR sensitizer screen. Utilizing the Broad Institute’s Cancer Dependency Map (DepMap), we identified EZH2, a core member of the PRC2 complex, as a co-dependency with the SAGA complex in neuroblastoma. Furthermore, we conducted a CRISPR/Cas9 screen with a focused sgRNA library (1,350 genes) to identify additional epigenetic sensitizers and drivers of resistance in neuroblastoma cells treated with GSK699. EZH2 knockout scored as sensitizing to GSK699 while knockout of BRD2, a member of the BET family of proteins and an epigenetic reader, scored as rendering resistance to GSK699. The utilization of both in vitro and preclinical studies confirmed that pharmacological inhibition of KAT2A/B using GSK699 and EZH2 using tazemetostat induced a combinatorial inhibitory effect on neuroblastoma tumor proliferation compared to single agent treatment, with marked prolongation of survival in xenograft models with combination therapy. Transcriptional analysis of tumors treated with combination therapy showed increases in epithelial to mesenchymal transition (EMT) programs and myogenesis differentiation pathways, a surprising finding under active investigation. In conclusion, our data demonstrates that inhibition of the SAGA complex in combination with EZH2 inhibition effectively suppresses the proliferation of MYCN-amplified neuroblastoma supporting further evaluation of this combination in models of neuroblastoma, including deeper mechanistic studies. Citation Format: Melinda Soeung, Kenneth Ross, Lucy Merickel, Silvi Salhotra, Audrey Taillon, Allen Basanthakumar, Kimberly Stegmaier. Combination Therapeutic Targeting of Chromatin Complexes in Neuroblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2):Abstract nr A043.