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Resistance to lysosomotropic drugs used to treat kidney and breast cancers involves autophagy and inflammation and converges in inducing CXCL5
Lysosomotropic agents such as sunitinib, lapatinib, and chloroquine belong to a drug family that is being used more frequently to treat advanced cancers. Sunitinib is standard care for metastatic renal cell carcinomas (mRCC) and lapatinib is used for trastuzumab/pertuzumab-refractory cancers. Howeve...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401402/ https://www.ncbi.nlm.nih.gov/pubmed/30867824 http://dx.doi.org/10.7150/thno.29093 |
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author | Giuliano, Sandy Dufies, Maeva Ndiaye, Papa Diogop Viotti, Julien Borchiellini, Delphine Parola, Julien Vial, Valérie Cormerais, Yann Ohanna, Mickaël Imbert, Véronique Chamorey, Emmanuel Rioux-Leclercq, Nathalie Savina, Ariel Ferrero, Jean-Marc Mograbi, Baharia Pagès, Gilles |
author_facet | Giuliano, Sandy Dufies, Maeva Ndiaye, Papa Diogop Viotti, Julien Borchiellini, Delphine Parola, Julien Vial, Valérie Cormerais, Yann Ohanna, Mickaël Imbert, Véronique Chamorey, Emmanuel Rioux-Leclercq, Nathalie Savina, Ariel Ferrero, Jean-Marc Mograbi, Baharia Pagès, Gilles |
author_sort | Giuliano, Sandy |
collection | PubMed |
description | Lysosomotropic agents such as sunitinib, lapatinib, and chloroquine belong to a drug family that is being used more frequently to treat advanced cancers. Sunitinib is standard care for metastatic renal cell carcinomas (mRCC) and lapatinib is used for trastuzumab/pertuzumab-refractory cancers. However, patients ineluctably relapse with a delay varying from a few months to a few years. To improve reactivity prior to relapse it is essential to identify the mechanisms leading to such variability. We showed previously that sunitinib became sequestered in lysosomes because of its basic pKa. Methods: Modifications to gene expression in response to sunitinib and in sunitinib resistant cells were analyzed by transcriptomic and proteomic analysis. ROS production was evaluated by FACS. Nuclear Factor kappa B (NFkB)-dependent transcriptional regulation of inflammatory gene expression was evaluated with a reporter gene. Correlation of CXCL5 with survival was analyzed with an online available data base (TCGA) and using a cohort of patients enrolled in the SUVEGIL clinical trial (NCT00943839). Results: We now show that sunitinib sequestration in lysosomes induced an incomplete autophagic process leading to activation of the NFkB inflammatory pathway. We defined a subset of inflammatory cytokines that were up-regulated by the drug either after an acute or chronic stimulus. One of the most up-regulated genes in sunitinib-resistant cells was the CXCL5 cytokine. CXCL5 was also induced in RCC by chloroquine and in a model of HER2 positive breast cancer cell lines after acute or chronic treatment with lapatinib. CXCL5 correlated to shorter survival in RCC and to the most aggressive forms of breast cancers. The levels of CXCL5 present in the plasma of patients treated with sunitinib were predictive of the efficacy of sunitinib but not of the VEGF-directed antibody bevacizumab. Conclusion: This translational study identified CXCL5 as a biomarker of efficacy of lysosomotropic drugs, a potential asset for personalized medicine. |
format | Online Article Text |
id | pubmed-6401402 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-64014022019-03-13 Resistance to lysosomotropic drugs used to treat kidney and breast cancers involves autophagy and inflammation and converges in inducing CXCL5 Giuliano, Sandy Dufies, Maeva Ndiaye, Papa Diogop Viotti, Julien Borchiellini, Delphine Parola, Julien Vial, Valérie Cormerais, Yann Ohanna, Mickaël Imbert, Véronique Chamorey, Emmanuel Rioux-Leclercq, Nathalie Savina, Ariel Ferrero, Jean-Marc Mograbi, Baharia Pagès, Gilles Theranostics Research Paper Lysosomotropic agents such as sunitinib, lapatinib, and chloroquine belong to a drug family that is being used more frequently to treat advanced cancers. Sunitinib is standard care for metastatic renal cell carcinomas (mRCC) and lapatinib is used for trastuzumab/pertuzumab-refractory cancers. However, patients ineluctably relapse with a delay varying from a few months to a few years. To improve reactivity prior to relapse it is essential to identify the mechanisms leading to such variability. We showed previously that sunitinib became sequestered in lysosomes because of its basic pKa. Methods: Modifications to gene expression in response to sunitinib and in sunitinib resistant cells were analyzed by transcriptomic and proteomic analysis. ROS production was evaluated by FACS. Nuclear Factor kappa B (NFkB)-dependent transcriptional regulation of inflammatory gene expression was evaluated with a reporter gene. Correlation of CXCL5 with survival was analyzed with an online available data base (TCGA) and using a cohort of patients enrolled in the SUVEGIL clinical trial (NCT00943839). Results: We now show that sunitinib sequestration in lysosomes induced an incomplete autophagic process leading to activation of the NFkB inflammatory pathway. We defined a subset of inflammatory cytokines that were up-regulated by the drug either after an acute or chronic stimulus. One of the most up-regulated genes in sunitinib-resistant cells was the CXCL5 cytokine. CXCL5 was also induced in RCC by chloroquine and in a model of HER2 positive breast cancer cell lines after acute or chronic treatment with lapatinib. CXCL5 correlated to shorter survival in RCC and to the most aggressive forms of breast cancers. The levels of CXCL5 present in the plasma of patients treated with sunitinib were predictive of the efficacy of sunitinib but not of the VEGF-directed antibody bevacizumab. Conclusion: This translational study identified CXCL5 as a biomarker of efficacy of lysosomotropic drugs, a potential asset for personalized medicine. Ivyspring International Publisher 2019-01-30 /pmc/articles/PMC6401402/ /pubmed/30867824 http://dx.doi.org/10.7150/thno.29093 Text en © Ivyspring International Publisher This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
spellingShingle | Research Paper Giuliano, Sandy Dufies, Maeva Ndiaye, Papa Diogop Viotti, Julien Borchiellini, Delphine Parola, Julien Vial, Valérie Cormerais, Yann Ohanna, Mickaël Imbert, Véronique Chamorey, Emmanuel Rioux-Leclercq, Nathalie Savina, Ariel Ferrero, Jean-Marc Mograbi, Baharia Pagès, Gilles Resistance to lysosomotropic drugs used to treat kidney and breast cancers involves autophagy and inflammation and converges in inducing CXCL5 |
title | Resistance to lysosomotropic drugs used to treat kidney and breast cancers involves autophagy and inflammation and converges in inducing CXCL5 |
title_full | Resistance to lysosomotropic drugs used to treat kidney and breast cancers involves autophagy and inflammation and converges in inducing CXCL5 |
title_fullStr | Resistance to lysosomotropic drugs used to treat kidney and breast cancers involves autophagy and inflammation and converges in inducing CXCL5 |
title_full_unstemmed | Resistance to lysosomotropic drugs used to treat kidney and breast cancers involves autophagy and inflammation and converges in inducing CXCL5 |
title_short | Resistance to lysosomotropic drugs used to treat kidney and breast cancers involves autophagy and inflammation and converges in inducing CXCL5 |
title_sort | resistance to lysosomotropic drugs used to treat kidney and breast cancers involves autophagy and inflammation and converges in inducing cxcl5 |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401402/ https://www.ncbi.nlm.nih.gov/pubmed/30867824 http://dx.doi.org/10.7150/thno.29093 |
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