IL-1-driven Signaling Promotes Resistance to PI3K and BCL2 Inhibitors in B-cell Lymphoma Preclinical Models.

Abstract Background: IL-1 is a central inflammatory cytokine with context-dependent effects in B-cell lymphomas, capable of supporting anti-tumor immunity but also promoting a pro-tumorigenic microenvironment. Here, we investigated the role of IL-1 in driving resistance to PI3K and BCL2 inhibitors in B-cell lymphoma preclinical. Methods: Cell lines, including derivatives with acquired resistance to PI3K/BCL2 inhibitors obtained by long exposure to the PI3K inhibitor copanlisib in the marginal zone lymphoma (MZL) cell line VL51 (Arribas, ENA 2020), were analyzed using transcriptomics, proteomics, and immunoblotting. Functional assays assessed drug sensitivity, pathway activation, cytokine responses, and the impact of IL-1 stimulation and blockade. A 1,400-compound FDA-approved library was used in combination with copanlisib/venetoclax. Results: VL51 cells with acquired resistance to PI3K/BCL2 inhibitors were characterized by an upregulation of IL1α and IL1β, elevated ERK and STAT3 phosphorylation, and increased expression of pro-survival and cytokine-responsive proteins. Recombinant IL-1α and IL-1β activated NF-κB and Ox-Phos in parental cells. IL-1α induced MYC and SRC targets, while IL-1β activated PI3K and STAT signaling. Either IL-1α or IL-1β reduced sensitivity to PI3K and BCL2 inhibitors in models of MZL (VL51, ESKOL), mantle cell lymphoma (REC1), and diffuse large B-cell lymphoma (OCI-Ly10). IL-1R1 blockade restored drug response. Notably, the combination of both IL-1α and IL-1β further enhanced resistance to copanlisib and to the BCL2 inhibitor venetoclax in VL51 cells. IL-1R1 blockade restored drug response. Notably, the combination of both IL-1α and IL-1β further enhanced the resistance to copanlisib and venetoclax in VL51. The drug-screen identified compounds targeting WNT, CDK, HDAC, HSP, PLK, ALDH1, AURKA, proton pump function, and microtubule dynamics that improved treatment efficacy, particularly in resistant cells. Validation studies demonstrated that several inhibitors effectively counteracted IL-1-associated resistance. The ALDH1 inhibitor disulfiram strongly restored copanlisib/venetoclax sensitivity in resistant models. Additional combinations, including ganetespib, rigosertib, panobinostat, alisertib, and AZ6102, also enhanced responses, indicating that IL-1-responsive stress, epigenetic, and mitotic pathways represent actionable vulnerabilities. Conclusions: IL-1-driven reprogramming promotes resistance to PI3K and BCL2 inhibition in B-cell lymphoma via activation of NF-κB, STAT3, and metabolic survival pathways. Targeting IL-1 signaling or downstream effectors may overcome resistance and offer a promising therapeutic strategy for relapsed or refractory B-cell lymphomas. Citation Format: Alberto J. Arribas, Federica Fuzio, Eleonora Cannas, Michela Chiappa, Luciano Cascione, Giulio Sartori, FIlippo Spriano, Andrea Rinaldi, Georg Stussi, Emanuele Zucca, Davide Rossi, Anastasios Stathis, Andrea Alimonti, Giovanna Damia, Massimo Broggini, Francesco Bertoni. IL-1-driven signaling promotes resistance to PI3K and BCL2 inhibitors in B-cell lymphoma preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1848.