Resistance to PI3Kδ inhibitors in marginal zone lymphoma can be reverted by targeting the IL-6/PDGFRA axis

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...

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Authors: Arribas, Alberto|||0000-0003-3123-6203, Napoli, Sara, Cascione, Luciano|||0000-0002-4606-0637, Sartori, Giulio, Barnabei, Laura, Gaudio, Eugenio, Tarantelli, Chiara, Mensah, Afua Adjeiwaa, Spriano, Filippo, Zucchetto, Antonella, Rossi, Francesca M, Rinaldi, Andrea, Castro de Moura, Manuel|||0000-0002-8488-5306, Jovic, Sandra, Bordone-Pittau, Roberta, Di Veroli, Alessandra, Stathis, Anastasios, Cruciani, Gabriele, Stüssi, Georg, Gattei, Valter, Brown, Jennifer R, Esteller, M|||0000-0003-4490-6093, Zucca, Emanuele|||0000-0002-5522-6109, Rossi, Davide, Bertoni, Francesco
Format: article
Publication Date:2022
Country:España
Institution:Universitat Autònoma de Barcelona
Repository:Dipòsit Digital de Documents de la UAB
Language:English
OAI Identifier:oai:ddd.uab.cat:270508
Online Access:https://ddd.uab.cat/record/270508
https://dx.doi.org/urn:doi:10.3324/haematol.2021.279957
Access Level:Open access
Keyword:Humans
Interleukin-6
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, B-Cell, Marginal Zone
MicroRNAs
Protein Kinase Inhibitors
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oai_identifier_str oai:ddd.uab.cat:270508
network_acronym_str ES
network_name_str España
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spelling Resistance to PI3Kδ inhibitors in marginal zone lymphoma can be reverted by targeting the IL-6/PDGFRA axisArribas, Alberto|||0000-0003-3123-6203Napoli, SaraCascione, Luciano|||0000-0002-4606-0637Sartori, GiulioBarnabei, LauraGaudio, EugenioTarantelli, ChiaraMensah, Afua AdjeiwaaSpriano, FilippoZucchetto, AntonellaRossi, Francesca MRinaldi, AndreaCastro de Moura, Manuel|||0000-0002-8488-5306Jovic, SandraBordone-Pittau, RobertaDi Veroli, AlessandraStathis, AnastasiosCruciani, GabrieleStüssi, GeorgGattei, ValterBrown, Jennifer REsteller, M|||0000-0003-4490-6093Zucca, Emanuele|||0000-0002-5522-6109Rossi, DavideBertoni, FrancescoHumansInterleukin-6Leukemia, Lymphocytic, Chronic, B-CellLymphoma, B-Cell, Marginal ZoneMicroRNAsProtein Kinase InhibitorsPI3Kδ 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 tumorsUniversitat Autònoma de Barcelona 22022-01-0120222022-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/270508https://dx.doi.org/urn:doi:10.3324/haematol.2021.279957reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengopen accesshttp://purl.org/coar/access_right/c_abf2Aquest 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.https://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2705082026-06-06T12:50:31Z
dc.title.none.fl_str_mv Resistance to PI3Kδ inhibitors in marginal zone lymphoma can be reverted by targeting the IL-6/PDGFRA axis
title Resistance to PI3Kδ inhibitors in marginal zone lymphoma can be reverted by targeting the IL-6/PDGFRA axis
spellingShingle Resistance to PI3Kδ inhibitors in marginal zone lymphoma can be reverted by targeting the IL-6/PDGFRA axis
Arribas, Alberto|||0000-0003-3123-6203
Humans
Interleukin-6
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, B-Cell, Marginal Zone
MicroRNAs
Protein Kinase Inhibitors
title_short Resistance to PI3Kδ inhibitors in marginal zone lymphoma can be reverted by targeting the IL-6/PDGFRA axis
title_full Resistance to PI3Kδ inhibitors in marginal zone lymphoma can be reverted by targeting the IL-6/PDGFRA axis
title_fullStr Resistance to PI3Kδ inhibitors in marginal zone lymphoma can be reverted by targeting the IL-6/PDGFRA axis
title_full_unstemmed Resistance to PI3Kδ inhibitors in marginal zone lymphoma can be reverted by targeting the IL-6/PDGFRA axis
title_sort Resistance to PI3Kδ inhibitors in marginal zone lymphoma can be reverted by targeting the IL-6/PDGFRA axis
dc.creator.none.fl_str_mv Arribas, Alberto|||0000-0003-3123-6203
Napoli, Sara
Cascione, Luciano|||0000-0002-4606-0637
Sartori, Giulio
Barnabei, Laura
Gaudio, Eugenio
Tarantelli, Chiara
Mensah, Afua Adjeiwaa
Spriano, Filippo
Zucchetto, Antonella
Rossi, Francesca M
Rinaldi, Andrea
Castro de Moura, Manuel|||0000-0002-8488-5306
Jovic, Sandra
Bordone-Pittau, Roberta
Di Veroli, Alessandra
Stathis, Anastasios
Cruciani, Gabriele
Stüssi, Georg
Gattei, Valter
Brown, Jennifer R
Esteller, M|||0000-0003-4490-6093
Zucca, Emanuele|||0000-0002-5522-6109
Rossi, Davide
Bertoni, Francesco
author Arribas, Alberto|||0000-0003-3123-6203
author_facet Arribas, Alberto|||0000-0003-3123-6203
Napoli, Sara
Cascione, Luciano|||0000-0002-4606-0637
Sartori, Giulio
Barnabei, Laura
Gaudio, Eugenio
Tarantelli, Chiara
Mensah, Afua Adjeiwaa
Spriano, Filippo
Zucchetto, Antonella
Rossi, Francesca M
Rinaldi, Andrea
Castro de Moura, Manuel|||0000-0002-8488-5306
Jovic, Sandra
Bordone-Pittau, Roberta
Di Veroli, Alessandra
Stathis, Anastasios
Cruciani, Gabriele
Stüssi, Georg
Gattei, Valter
Brown, Jennifer R
Esteller, M|||0000-0003-4490-6093
Zucca, Emanuele|||0000-0002-5522-6109
Rossi, Davide
Bertoni, Francesco
author_role author
author2 Napoli, Sara
Cascione, Luciano|||0000-0002-4606-0637
Sartori, Giulio
Barnabei, Laura
Gaudio, Eugenio
Tarantelli, Chiara
Mensah, Afua Adjeiwaa
Spriano, Filippo
Zucchetto, Antonella
Rossi, Francesca M
Rinaldi, Andrea
Castro de Moura, Manuel|||0000-0002-8488-5306
Jovic, Sandra
Bordone-Pittau, Roberta
Di Veroli, Alessandra
Stathis, Anastasios
Cruciani, Gabriele
Stüssi, Georg
Gattei, Valter
Brown, Jennifer R
Esteller, M|||0000-0003-4490-6093
Zucca, Emanuele|||0000-0002-5522-6109
Rossi, Davide
Bertoni, Francesco
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universitat Autònoma de Barcelona
dc.subject.none.fl_str_mv Humans
Interleukin-6
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, B-Cell, Marginal Zone
MicroRNAs
Protein Kinase Inhibitors
topic Humans
Interleukin-6
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, B-Cell, Marginal Zone
MicroRNAs
Protein Kinase Inhibitors
description 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
publishDate 2022
dc.date.none.fl_str_mv 2
2022-01-01
2022
2022-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/270508
https://dx.doi.org/urn:doi:10.3324/haematol.2021.279957
url https://ddd.uab.cat/record/270508
https://dx.doi.org/urn:doi:10.3324/haematol.2021.279957
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by-nc/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by-nc/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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