Abstract 612: Antimicrobial peptides with antitumor activity against marginal zone lymphoma cell lines resistant to BTK, PI3K, and BCL2 inhibitors

Abstract Background: Antimicrobial peptides (AMPs) are a class of small proteins produced by all living organisms, from prokaryotes to humans. In higher eukaryotes, AMPs contribute to the host's innate immunity, promptly responding against any pathogen. Due to their mechanism of action, represented mainly by their ability to bind and perturb microbial membranes, AMPs are being explored as novel agents against multidrug-resistant bacteria and anti-cancer agents. Natural peptides could be used as a scaffold to design new AMPs with improved effectiveness, stability, and selectivity. Marginal zone lymphoma (MZL) is an indolent yet incurable B-cell lymphoid tumor. Here, we assessed the antitumor activity of seven AMPs in MZL models with acquired resistance to FDA-approved BTK, PI3K, and BCL2 inhibitors. Methods: Established human cell lines derived from MZL (VL51, Karpas1718) and derivatives with secondary resistance to targeted agents obtained by long drug exposure (n.=3 from VL51, n.=1 from Karpas1718 (Arribas et al, Haematologica 2022; Mol Cancer Ther 2024; ENA 2019; ENA 2020) were exposed to increasing concentrations of AMPs or DMSO, as control. Anti-proliferative activity was assessed by MTT assay after 72 hours of exposure. Results: MZL cell lines were exposed to AMPs originating from Antarctic fishes (Chionodraco hamatus, Trematomus bernacchii; trematocines, n.=2; chionodracines, n.=1) and amphibians (temporins, n.=4;). Anti-proliferative activity was observed in parental MZL with two synthetic AMPs: a Trematomus bernacchii - derived trematocine mutant (Della Pelle et al, Antibiotics 2020), with IC50 values of 7.5 μM in VL51 and 10 μM in Karpas1718 and the Rana temporaria - derived Temporin L (Simmaco et al, Eur J Biochem 1996) with IC50 of 8 μM in VL51 and 15 μM in Karpas1718. Notably, the antiproliferative activity was maintained in all the derivative MZL cell lines with resistance to BTK, PI3K, and BCL2 inhibitors. At higher concentrations, also the other trematocine (Karpas1718 models) and all the temporins (VL51 and Karpas1718 models) had anti-proliferative activity (IC50 values 25-50 μM). Conclusions: AMPs derived from Antarctic fishes and amphibians have in vitro anti-tumor activity in cell lines derived from MZL, including models with acquired resistance to BTK, PI3K, and BCL2 inhibitors. AMPs and their synthetic derivatives can provide novel anti-lymphoma agents with mechanisms of action deeply different from currently used drugs. Citation Format: Filippo Spriano, Alberto J. Arribas, Fangwen Zhang, Maria Luisa Mangoni, Francesco Buonocore, Francesco Bertoni. Antimicrobial peptides with antitumor activity against marginal zone lymphoma cell lines resistant to 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 612.