High-Throughput Screening Identifies PLK1 Inhibition as a Strategy to Potentiate BTK Blockade in Marginal Zone Lymphoma

Le résumé fourni par la source

Abstract B-cell receptor (BCR) signaling is a key therapeutic target in B-cell lymphomas, and Bruton tyrosine kinase inhibitors (BTKi) have demonstrated clinical efficacy in marginal zone lymphoma (MZL). However, the rate of complete remissions is relatively low, and resistance remains a significant clinical challenge, underscoring the need for novel combination strategies. To identify compounds that enhance the activity of BTKi and overcome resistance, we conducted a high-throughput screen of 1,695 compounds using a previously developed MZL model of acquired resistance to BTK and PI3K inhibitors derived from the Karpas1718 cell line. Thirty-three compounds showed single-agent anti-proliferative activity in the nanomolar range, both in the Karpas1718-resistant and parental cells. Based on their clinical potential in combination with BTKi, seven compounds were selected for further validation. The polo-like kinase 1 (PLK1) inhibitor rigosertib emerged as a top candidate, showing strong activity in both parental and BTKi-resistant cell lines. Combination treatment of rigosertib and BTKi zanubrutinib resulted in broad transcriptomic changes, characterized by the downregulation of pathways involved in B-cell activation, proliferation, and BCR signaling. Mechanistically, the combination reduced phosphorylation of key BCR pathway components and inhibited NF-κB nuclear translocation. These findings suggest that PLK1 inhibition can overcome BTKi resistance by further inhibiting BCR signaling through the canonical NF-κB pathway. Therefore, the dual pharmacological inhibition of BTK and PLK1 is a promising therapeutic approach for patients with MZL and warrants further preclinical and clinical investigations.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.