Abstract 5410: CDK9 pharmacological inhibition has antitumor activity in marginal zone lymphoma models and can improve the effects of BTK, PI3K, and BCL2 inhibitors

Abstract Background: CDK9 inhibition rapidly down-regulates oncogenes, such as MYC, MCL1, PIM and PI3Ks. Indeed, CDK9 inhibitors, either as a single agent or in combination, can decrease proliferation and induce apoptosis in preclinical models of B cell lymphomas and show promising early signs of activity in B cell lymphoma patients (Diamond et al, CCR 2022; Frigault et al, Can Res Com 2023; Jiang et al, Biomark Res 2024). PRT2527 is a highly selective, ATP-competitive, CDK9 inhibitor with preclinical activity in diffuse large B cell lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia (Fultang et al, AACR 2024). PRT2527 has shown favorable tolerability, with manageable toxicity in a phase 1 study for solid tumor patients (Patel et al, ENA 2023), and it is now in phase 1 as a single agent and in combination with the BTK inhibitor zanubrutinib for hematological cancers patients (NCT05665530). Here, we studied PRT2527 in models derived from marginal zone lymphoma (MZL), including derivatives with acquired resistance to PI3K, BTK, and BCL2 inhibitors. Methods: MZL cell lines (VL51, Karpas1718, SSK41, ESKOL, HC1, HAIRM) and their derivatives with secondary resistance to targeted agents obtained by long drug exposure (n.=3 from VL51, n.=1 from Karpas1718, n.=1 from SSK41; Arribas et al, Haematologica 2022, Mol Cancer Ther 2024, ENA 2019, ENA 2020, AACR 2024) were exposed to increasing concentrations of PRT2527 or DMSO (control) for 4 h and then washed out. Anti-proliferative activity was then assessed by MTT assay after 48 h. Results: Despite the limited exposure time, CDK9 inhibitor PRT2527 exhibited antiproliferative activity in the nM range (average IC50 724nM; 95%CI, 467-981) across the MZL models. The anti-tumor activity was maintained in MZL cell lines with acquired resistance to PI3K, BTK, and BCL2 inhibitors. The combination of PRT2527 with the PI3K inhibitor idelalisib, with the BTK inhibitor ibrutinib, or triple combination with the PI3K inhibitor copanlisib and the BCL2 inhibitor venetoclax was beneficial in all parental cells, and the benefit was maintained, although reduced, in derivatives with acquired resistance to PI3K and BTK inhibitors. Only the VL51 model with resistance to copanlisib/venetoclax benefited from the addition of PRT2527 in the VL51 model, while no advantage was observed with the triple combination in the SSK41 derivative. Conclusions: CDK9 inhibition with PRT2527 has in vitro antitumor activity in MZL models, which is maintained in models with acquired resistance to PI3K, BTK, or BCL2 inhibitors. CDK9 inhibition with PRT2527 can improve the sensitivity of MZL cells to BTK, PI3K, and BCL2 inhibitors. Citation Format: Alberto J. Arribas, Eleonora Cannas, Davide Rossi, Anastasios Stathis, Diane Heiser, Francesco Bertoni. CDK9 pharmacological inhibition has antitumor activity in marginal zone lymphoma models and can improve the effects of BTK, PI3K, and BCL2 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5410.