Resistance to PI3Kδ inhibitors in marginal zone lymphoma can be reverted by targeting the IL-6/PDGFRA axis
Arribas, Alberto J (SIB Swiss Institute of Bioinformatics)
Napoli, Sara (Università della Svizzera Italiana)
Cascione, Luciano (SIB Swiss Institute of Bioinformatics)
Sartori, Giulio (Università della Svizzera Italiana)
Barnabei, Laura (Università della Svizzera Italiana)
Gaudio, Eugenio (Università della Svizzera Italiana)
Tarantelli, Chiara (Università della Svizzera Italiana)
Mensah, Afua Adjeiwaa (Università della Svizzera Italiana)
Spriano, Filippo (Università della Svizzera Italiana)
Zucchetto, Antonella (Centro di Riferimento Oncologico di Aviano)
Rossi, Francesca M (Centro di Riferimento Oncologico di Aviano)
Rinaldi, Andrea (Università della Svizzera Italiana)
Castro de Moura, Manuel (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Jovic, Sandra (Università della Svizzera italiana)
Bordone-Pittau, Roberta (Oncology Institute of Southern Switzerland)
Di Veroli, Alessandra (University of Perugia)
Stathis, Anastasios (Università della Svizzera Italiana)
Cruciani, Gabriele (University of Perugia)
Stussi, Georg (Oncology Institute of Southern Switzerland)
Gattei, Valter (Centro di Riferimento Oncologico di Aviano)
Brown, Jennifer R (Harvard Medical School)
Esteller, M (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Zucca, Emanuele (Oncology Institute of Southern Switzerland)
Rossi, Davide (Oncology Institute of Southern Switzerland)
Bertoni, Francesco (Oncology Institute of Southern Switzerland)
Universitat Autònoma de Barcelona

Date:	2022
Abstract:	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.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Humans ; Interleukin-6 ; Leukemia, Lymphocytic, Chronic, B-Cell ; Lymphoma, B-Cell, Marginal Zone ; MicroRNAs ; Protein Kinase Inhibitors
Published in:	Haematologica, Vol. 107 Núm. 11 (november 2022) , p. 2685-2697, ISSN 1592-8721

DOI: 10.3324/haematol.2021.279957
PMID: 35484662

13 p, 1.6 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
Articles > Research articles
Articles > Published articles