TY - JOUR AU - Arribas, Alberto J. AU - Napoli, Sara AU - Cascione, Luciano AU - Sartori, Giulio AU - Barnabei, Laura AU - Gaudio, Eugenio AU - Tarantelli, Chiara AU - Mensah, Afua Adjeiwaa AU - Spriano, Filippo AU - Zucchetto, Antonella AU - Rossi, Francesca M AU - Rinaldi, Andrea AU - Castro de Moura, Manuel AU - Jovic, Sandra AU - Bordone-Pittau, Roberta AU - Di Veroli, Alessandra AU - Stathis, Anastasios AU - Cruciani, Gabriele AU - Stussi, Georg AU - Gattei, Valter AU - Brown, Jennifer R. AU - Esteller, Manel AU - Zucca, Emanuele AU - Rossi, Davide AU - Bertoni, Francesco PY - 2022/10/31 Y2 - 2024/03/28 TI - Resistance to PI3Kδ inhibitors in marginal zone lymphoma can be reverted by targeting the IL-6/PDGFRA axis JF - Haematologica JA - haematol VL - 107 IS - 11 SE - Articles DO - 10.3324/haematol.2021.279957 UR - https://haematologica.org/article/view/haematol.2021.279957 SP - 2685-2697 AB - PI3Kδ inhibitors are active in patients with lymphoid neoplasms and a first series of them have been approved for the treatment of multiple types of B-cell lymphoid tumors, including marginal zone lymphoma (MZL). The identification of the mechanisms underlying either primary or secondary resistance is fundamental to optimize the use of novel drugs. Here we present a model of secondary resistance to PI3Kδ inhibitors obtained by prolonged exposure of a splenic MZL cell line to idelalisib. The VL51 cell line was kept under continuous exposure to idelalisib. The study included detailed characterization of the model, pharmacological screens, silencing experiments, and validation experiments on multiple cell lines and on clinical specimens. VL51 developed resistance to idelalisib, copanlisib, duvelisib, and umbralisib. An integrative analysis of transcriptome and methylation data highlighted an enrichment of upregulated transcripts and low-methylated promoters in resistant cells, including IL-6/STAT3- and PDGFRA-related genes and surface CD19 expression, alongside the repression of the let-7 family of miRNA, and miR-125, miR-130, miR-193 and miR-20. The IL-6R blocking antibody tocilizumab, the STAT3 inhibitor stattic, the LIN28 inhibitor LIN1632, the PDGFR inhibitor masitinib and the anti-CD19 antibody drug conjugate loncastuximab tesirine were active compounds in the resistant cells as single agents and/or in combination with PI3Kδ inhibition. Findings were validated on additional in vitro lymphoma models and on clinical specimens. A novel model of resistance obtained from splenic MZL allowed the identification of therapeutic approaches able to improve the antitumor activity of PI3Kδ inhibitors in B-cell lymphoid tumors. ER -