Open AccessResistance to PI3Kδ inhibitors in marginal zone lymphoma can be reverted by targeting the IL-6/PDGFRA axis
Author(s) -
Alberto J. Arribas,
Sara Napoli,
Luciano Cascione,
Giulio Sartori,
Laura Barnabei,
Eugenio Gaudio,
Chiara Tarantelli,
Afua A. Mensah,
Filippo Spriano,
Antonella Zucchetto,
Francesca Maria Rossi,
Andrea Rinaldi,
Manuel Castro de Moura,
Sandra Jovic,
Roberta Bordone-Pittau,
Alessandra Di Veroli,
Anastasios Stathis,
Gabriele Cruciani,
Georg Stüssi,
Valter Gattei,
Jennifer R. Brown,
Manel Esteller,
Emanuele Zucca,
Davide Rossi,
Francesco Bertoni
Publication year - 2022
Publication title -
haematologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.782
H-Index - 142
eISSN - 1592-8721
pISSN - 0390-6078
DOI - 10.3324/haematol.2021.279957
Subject(s) - idelalisib , cancer research , pi3k/akt/mtor pathway , biology , ibrutinib , immunology , leukemia , chronic lymphocytic leukemia , signal transduction , microbiology and biotechnology
PI3KPPinhibitors 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 PI3Kffinhibitors 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, 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 underlined an enrichment of up-regulated transcripts and lowmethylated promoters in resistant cells, including IL-6/STAT3 and PDGFRA related genes and surface CD19 expression, alongside the repression of the let-7 family miRNAs, of miR-125, miR-130, miR-193 and miR-20. The use of 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 PI3K//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 anti-tumor activity of PI3Kttinhibitors in B-cell lymphoid tumors.