Abstract A073 Epigenetic control of neuroblastoma differentiation through inhibition of the histone acetyltransferases KAT6A and KAT6B

Abstract Retinoic acid re-organizes the enhancers regulating the expression of these key transcription factors in neuroblastoma and establishes a new differentiated cell state characterized by MYCN downregulation and proliferative arrest. However, the epigenetic and growth suppressing effects of retinoic acid are completely reversible in vitro, leading to cell proliferation. We sought to determine if retinoid-induced differentiation can be forced to progress to terminal neuronal maturation by the addition of inhibitors of enzymes modifying the epigenome. We conducted a drug screen using more than 450 epigenetic modifiers to treat neuroblastoma cells either with each compound alone or in combination with retinoic acid to determine whether any compound augments the antiproliferative effects of retinoic acid. We found that an inhibitor of the histone acetyltransferases KAT6A/B synergistically inhibits neuroblastoma growth in combination with retinoic acid in vitro and enhances neuroblastoma differentiation. We used a xenograft model of retinoid-sensitive neuroblastoma cells in mice to test if the combination treatment with isotretinoin and a KAT6 inhibitor is more effective than isotretinoin alone to induce permanent neuroblastoma differentiation in vivo. We found that isotretinoin is very effective in suppressing neuroblastoma proliferation, however its effects are completely reversible upon drug removal leading to rapid tumor re-growth. In contrast, when isotretinoin is combined with a KAT6 inhibitor, tumors cannot re-grow after isotretinoin removal and remain differentiated. In conclusion, our studies nominate KAT6A/B inhibition combined with isotretinoin as a promising approach to improve outcome for patients with neuroblastoma. Citation Format: Nina Weichert-Leahey, Thomas Look. Epigenetic control of neuroblastoma differentiation through inhibition of the histone acetyltransferases KAT6A and KAT6B [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A073.