Abstract C027: Epigenetic vulnerabilities in marginal zone lymphoma

Abstract Background. Alterations in chromatin-associated proteins contribute to the rewiring of transcriptional networks, promoting lymphomagenesis, disease progression, and resistance to therapies. Thus, epigenetic modulators offer a promising therapeutic avenue. Marginal zone lymphoma (MZL) is characterized by methylation changes, recurrent mutations in genes encoding chromatin remodelers and transcription regulators. Epigenetic reprogramming can sustain resistance to targeted agents. To identify novel therapeutic targets in MZL, we took advantage of the Structural Genomics Consortium (SGC) collection of chemical probes that inhibit or antagonize proteins involved in epigenetic signaling (www.thesgc.org). We exposed MZL cell lines, including models of secondary resistance to BTK, BCL2 and PI3K inhibitors, to 46 epigenetic compounds, spanning molecules targeting bromodomain (BRD), methyltransferases (MT), lysine demethylases (KDM) and histone acetyltransferases (HAT). Methods. Cells were exposed to the SGC library compounds. Cell viability was assessed after 72h. Compounds giving >40% reduction in cell proliferation versus control were considered active. Selected hits were validated in full dose-response assays. Results. Two MZL cell lines (VL51, Karpas1718) and four derivatives with secondary resistance to BTK, PI3K, and BCL2 inhibitors (VL51-Ide, VL51-Copa, VL51-Ibru, Karpas1718-Ibru) were exposed to the SGC library compounds at 100 nM and 5 μM. Resistant derivatives were generally more sensitive to various epigenetic compounds than their parental cells. Only the BET inhibitor (i) JQ1 and the DOT1L-i SGC 0946 showed activity in the parental cells (both 100 nM and 5 μM, both models). Conversely, six compounds were active in resistant models at 100 nM: JQ1 and SGC 0946 (4/4), the PRMT5-i LLY 283 (2/4), and the BRPF2/TAF1-i BAY 299 (1/4). At 5 μM, 13 compounds were active: JQ1 and SGC 0946 in 4/4, 8 compounds in at least 2 models (targeting PRMT5, BRPF2/TAF1, G9a/GLP, JMJD3/UTX, BRD9, p300/CBP, EZH2) and 3 compounds in at least 1 model (PRMT7, p300/CBP, PRMT1/3/4/6/8). We then performed validation MTT experiments for 8 compounds (BAY 299, BI 9564, GSK 2801, I-BRD9, LLY 238, SGC 0946, SGC 3027, UNC 0642) using 6 concentrations of each molecule in all models. Higher activity in resistant derivatives was largely confirmed for the Karpas1718 model, and not in VL51, in which similar activity was seen in parental and resistant cells. The most active compounds were BAY 299 (BRPF2/TAF1; median IC50 6 nM), SGC 3027 (PRMT7; 229 nM) and SGC 0946 (DOT1L, 380 nM), exhibiting dose-dependent cytotoxicity across parental and resistant MZL models, followed by the others, all with median IC50s lower than or equal to 2 μM. Conclusions. Our findings reveal novel potential epigenetic vulnerabilities (PRMT7, DOT1L, and BRPF2/TAF1) in lymphoma models, also with acquired resistance to targeted therapies, besides confirming PRMT5 and BET bromodomains as valid targets. Compounds targeting these proteins should be further explored as single agents and in combinations. Citation Format: Alberto Jesus. Arribas, Luca Licenziato, Eleonora Cannas, Luca Aresu, Afua Adjeiwaa. Mensah, Francesco Bertoni. Epigenetic vulnerabilities in marginal zone lymphoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C027.