Abstract C024: CBP/EP300 inhibitor OPN-6602 in marginal zone lymphomas: preclinical activity as a single agent and in combination with BTK inhibition

Abstract Background. Chromatin accessibility is frequently disrupted in cancer cells, often as a result of deregulated activity of histone-modifying enzymes. The genes encoding the acetyltransferases CREBBP (CBP) and EP300 are recurrently mutated in multiple cancer types, including marginal zone lymphomas (MZLs). These mutations are typically heterozygous and mutually exclusive, suggesting that CBP and EP300 are essential for cancer cell survival. Consistently, pharmacological inhibition of CBP and EP300 has demonstrated anti-tumor activity in a range of solid and hematologic tumor models. OPN-6602 is a potent and selective, oral small-molecule CBP/EP300 bromodomain inhibitor that, evaluated in a screen of 91 cell types, demonstrated high activity in active in hematopoietic tumors (Matusow et al, ASH 2024). OPN-6602 is currently being tested in a Phase 1 trial (NCT06433947) in relapsed or refractory multiple myeloma (MM) patients. Here, we explored the anti-tumor activity of OPN-6602 in MZL cell lines, including models of secondary resistance to BTK inhibitors, as a single agent and in combination with ibrutinib. Methods. The effect on cell viability was assessed by MTT assay after exposure to increasing concentrations of compounds or DMSO (control) in MZL cell lines (VL51, Karpas1718, and SSK41) and in their derivatives with secondary resistance to BTK, PI3K, and BCL2 inhibitors. Results. We first studied OPN-6602 in three CBP/EP300 wild-type MZL cell lines. We observed a dose-dependent anti-proliferative effect with IC50 values in the nM range at 72 hours (SSK41, 2 nM; VL51, 5 nM; Karpas1718, 33 nM). We then moved to three models of resistance to BTK inhibitors obtained after long exposure to the BTK inhibitor ibrutinib (VL51-IBR), the PI3K-delta inhibitor idelalisib (Karpas1718-IDE), and the BCL2 inhibitor venetoclax (SSK41-VEN). CBP/EP300 inhibition still showed a dose-dependent anti-proliferative activity, albeit reduced when compared to the parental cells (VL51-IBR, 40 nM; Karpas1718-IDE, 70 nM; SSK41-VEN, 80 nM). When we combined OPN-6602 with the BTK inhibitor ibrutinib, we observed an additive or synergistic effect in all six models, as evaluated using the Cho-Talalay, ZIP, or HAS score. Conclusions. The CBP/EP300 inhibitor OPN-6602 has single-agent activity in MZL models, and it improves the anti-tumor activity of BTK pharmacological blockade. Our data support the clinical exploration of the compound also for MZL patients beyond the MM setting. Citation Format: Maidel Carpio, Alberto Jesus. Arribas, Davide Rossi, Bernice Matusow, Gideon Bollag, Francesco Bertoni. CBP/EP300 inhibitor OPN-6602 in marginal zone lymphomas: preclinical activity as a single agent and in combination with BTK inhibition [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 C024.