Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma

Platinum-based chemotherapy in combination with immune-checkpoint inhibitors is the current standard of care for patients with advanced lung adenocarcinoma (LUAD). However, tumor progression evolves in most cases. Therefore, predictive bioma ricers are needed for better patient stratification and fo...

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Autores: Nokin, Marie-Julie, Darbo, Elodie, Travert, Camille, Drogat, Benjamin, Lacouture, Aurélie, San José, Sonia, Cabrera, Nuria, Turcq, Béatrice, Prouzet-Mauleon, Valérie, Falcone, Mattia, Villanueva Garatachea, Alberto, Wang, Haiyun, Herfs, Michael, Mosteiro, Miguel, Jänne, Pasi A., Pujol, Jean-Louis, Maraver, Antonio, Barbacid, Mariano, Nadal, Ernest, Santamaria, David, Ambrogio, Chiara
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/173471
Acceso en línea:https://hdl.handle.net/2445/173471
Access Level:acceso abierto
Palabra clave:Càncer de pulmó
Quimioteràpia
Lung cancer
Chemotherapy
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spelling Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinomaNokin, Marie-JulieDarbo, ElodieTravert, CamilleDrogat, BenjaminLacouture, AurélieSan José, SoniaCabrera, NuriaTurcq, BéatriceProuzet-Mauleon, ValérieFalcone, MattiaVillanueva Garatachea, AlbertoWang, HaiyunHerfs, MichaelMosteiro, MiguelJänne, Pasi A.Pujol, Jean-LouisMaraver, AntonioBarbacid, MarianoNadal, ErnestSantamaria, DavidAmbrogio, ChiaraCàncer de pulmóQuimioteràpiaLung cancerChemotherapyPlatinum-based chemotherapy in combination with immune-checkpoint inhibitors is the current standard of care for patients with advanced lung adenocarcinoma (LUAD). However, tumor progression evolves in most cases. Therefore, predictive bioma ricers are needed for better patient stratification and for the identification of new therapeutic strategies, including enhancing the efficacy of chemotoxic agents. Here, we hypothesized that discoidin domain receptor 1 (DDR1) may be both a predictive factor for chemoresistance in patients with LUAD and a potential target positively selected in resistant cells. By using biopsies from patients with LUAD, KRAS-mutant LUAD cell lines, and in vivo genetically engineered KRAS-driven mouse models, we evaluated the role of DDR1 in the context of chemotherapy treatment. We found that DORT is upregulated during chemotherapy both in vitro and in viva. Moreover, analysis of a cohort of patients with LUAD suggested that high DOR1 levels in pretreatment biopsies correlated with poor response to chemotherapy. Additionally, we showed that combining DORI inhibition with chemotherapy prompted a synergistic therapeutic effect and enhanced cell death of KRAS-mutant tumors in vivo. Collectively, this study suggests a potential role for DDR1 as both a predictive and prognostic biomarker, potentially improving the chemotherapy response of patients with LUAD.American Society for Clinical Investigation Inc.2021202120202021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion13 p.application/pdfhttps://hdl.handle.net/2445/173471Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1172/jci.insight.137869JcCIInsight, 2020, vol. 5, num. 15https://doi.org/10.1172/jci.insight.137869(c) American Society for Clinical Investigation, 2020info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1734712026-05-29T05:05:01Z
dc.title.none.fl_str_mv Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma
title Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma
spellingShingle Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma
Nokin, Marie-Julie
Càncer de pulmó
Quimioteràpia
Lung cancer
Chemotherapy
title_short Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma
title_full Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma
title_fullStr Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma
title_full_unstemmed Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma
title_sort Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma
dc.creator.none.fl_str_mv Nokin, Marie-Julie
Darbo, Elodie
Travert, Camille
Drogat, Benjamin
Lacouture, Aurélie
San José, Sonia
Cabrera, Nuria
Turcq, Béatrice
Prouzet-Mauleon, Valérie
Falcone, Mattia
Villanueva Garatachea, Alberto
Wang, Haiyun
Herfs, Michael
Mosteiro, Miguel
Jänne, Pasi A.
Pujol, Jean-Louis
Maraver, Antonio
Barbacid, Mariano
Nadal, Ernest
Santamaria, David
Ambrogio, Chiara
author Nokin, Marie-Julie
author_facet Nokin, Marie-Julie
Darbo, Elodie
Travert, Camille
Drogat, Benjamin
Lacouture, Aurélie
San José, Sonia
Cabrera, Nuria
Turcq, Béatrice
Prouzet-Mauleon, Valérie
Falcone, Mattia
Villanueva Garatachea, Alberto
Wang, Haiyun
Herfs, Michael
Mosteiro, Miguel
Jänne, Pasi A.
Pujol, Jean-Louis
Maraver, Antonio
Barbacid, Mariano
Nadal, Ernest
Santamaria, David
Ambrogio, Chiara
author_role author
author2 Darbo, Elodie
Travert, Camille
Drogat, Benjamin
Lacouture, Aurélie
San José, Sonia
Cabrera, Nuria
Turcq, Béatrice
Prouzet-Mauleon, Valérie
Falcone, Mattia
Villanueva Garatachea, Alberto
Wang, Haiyun
Herfs, Michael
Mosteiro, Miguel
Jänne, Pasi A.
Pujol, Jean-Louis
Maraver, Antonio
Barbacid, Mariano
Nadal, Ernest
Santamaria, David
Ambrogio, Chiara
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Càncer de pulmó
Quimioteràpia
Lung cancer
Chemotherapy
topic Càncer de pulmó
Quimioteràpia
Lung cancer
Chemotherapy
description Platinum-based chemotherapy in combination with immune-checkpoint inhibitors is the current standard of care for patients with advanced lung adenocarcinoma (LUAD). However, tumor progression evolves in most cases. Therefore, predictive bioma ricers are needed for better patient stratification and for the identification of new therapeutic strategies, including enhancing the efficacy of chemotoxic agents. Here, we hypothesized that discoidin domain receptor 1 (DDR1) may be both a predictive factor for chemoresistance in patients with LUAD and a potential target positively selected in resistant cells. By using biopsies from patients with LUAD, KRAS-mutant LUAD cell lines, and in vivo genetically engineered KRAS-driven mouse models, we evaluated the role of DDR1 in the context of chemotherapy treatment. We found that DORT is upregulated during chemotherapy both in vitro and in viva. Moreover, analysis of a cohort of patients with LUAD suggested that high DOR1 levels in pretreatment biopsies correlated with poor response to chemotherapy. Additionally, we showed that combining DORI inhibition with chemotherapy prompted a synergistic therapeutic effect and enhanced cell death of KRAS-mutant tumors in vivo. Collectively, this study suggests a potential role for DDR1 as both a predictive and prognostic biomarker, potentially improving the chemotherapy response of patients with LUAD.
publishDate 2020
dc.date.none.fl_str_mv 2020
2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/173471
url https://hdl.handle.net/2445/173471
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1172/jci.insight.137869
JcCIInsight, 2020, vol. 5, num. 15
https://doi.org/10.1172/jci.insight.137869
dc.rights.none.fl_str_mv (c) American Society for Clinical Investigation, 2020
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) American Society for Clinical Investigation, 2020
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 13 p.
application/pdf
dc.publisher.none.fl_str_mv American Society for Clinical Investigation Inc.
publisher.none.fl_str_mv American Society for Clinical Investigation Inc.
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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