Dual inhibition of AURKA and ERBB overcomes resistance to PI3K/BTK/BCL2 inhibitors in marginal zone lymphoma models

Background : Despite recent therapeutic advances, resistance to targeted agents remains a major barrier to durable responses in B-cell lymphomas, including marginal zone lymphoma (MZL). Aurora kinase A (AURKA) inhibition has shown promise in overcoming chemotherapy resistance and improving outcomes in MYC-driven B-cell lymphomas (Park et al., 2019). In parallel, ERBB4 signaling mediates resistance to PI3K and BTK inhibitors through activation of the PI3K-AKT pathway (Arribas et al., 2024). The AURKA inhibitor alisertib is currently in clinical development, while the pan-ERBB inhibitor neratinib is FDA/EMA-approved for use across several malignancies, providing an opportunity for rapid translation. Here, we evaluated the antitumor activity and mechanisms of alisertib and neratinib, alone or combined with the BTK inhibitor ibrutinib, in MZL models with acquired resistance to PI3K/BTK/BCL2 inhibitors. Methods : MZL cell lines Karpas1718 and VL51, along with their derivatives resistant to PI3K/BTK/BCL2 inhibitors (Arribas et al., 2022; 2024; 2025), were treated with alisertib, neratinib, and ibrutinib individually or in combination. Cell viability, apoptosis, and immunoblotting assays were used to assess drug activity, synergy, and modulation of signaling pathways. Results : Alisertib and neratinib displayed strong, dose-dependent anti-lymphoma activity and maintained efficacy in models resistant to PI3K, BTK, and BCL2 inhibitors. Their combination with ibrutinib produced additive/synergistic effects, significantly enhancing apoptosis compared with ibrutinib alone, including in BTK-resistant cells. The alisertib/ibrutinib/neratinib triple combination induced the most profound suppression of cell growth, outperforming the dual-agent regimens. Mechanistically, triple therapy suppressed phosphorylation of AURKA and its downstream target, PLK1, reduced ERK activation, and downregulated the prosurvival protein MCL1. Notably, alisertib plus neratinib overcame ibrutinib resistance in both Karpas1718 and VL51, despite not directly enhancing BTK inhibition. Conclusions : Dual inhibition of AURKA and ERBB pathways with alisertib and neratinib synergizes with BTK blockade to overcome resistance to multiple targeted therapies in MZL. Given the clinical availability of neratinib and emerging safety data for alisertib, these findings highlight a therapeutically actionable strategy that could be rapidly advanced into early-phase trials for relapsed/refractory MZL. This combination approach may expand treatment options for patients with limited responses to current PI3K, BTK, or BCL2 inhibitors.