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Macrophage Migration Inhibitory Factor Is a Molecular Determinant of the Anti-EGFR Monoclonal Antibody Cetuximab Resistance in Human Colorectal Cancer Cells

Background: The clinical impact of the monoclonal antibody cetuximab targeting the EGFR in colorectal cancer (CRC) is widely recognized. Nevertheless, the onset of cetuximab resistance is a serious issue that limits the effectiveness of this drug in targeted therapies. Unraveling the molecular playe...

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Autores principales: Russo, Rosita, Matrone, Nunzia, Belli, Valentina, Ciardiello, Davide, Valletta, Mariangela, Esposito, Sabrina, Pedone, Paolo Vincenzo, Ciardiello, Fortunato, Troiani, Teresa, Chambery, Angela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826402/
https://www.ncbi.nlm.nih.gov/pubmed/31557914
http://dx.doi.org/10.3390/cancers11101430
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author Russo, Rosita
Matrone, Nunzia
Belli, Valentina
Ciardiello, Davide
Valletta, Mariangela
Esposito, Sabrina
Pedone, Paolo Vincenzo
Ciardiello, Fortunato
Troiani, Teresa
Chambery, Angela
author_facet Russo, Rosita
Matrone, Nunzia
Belli, Valentina
Ciardiello, Davide
Valletta, Mariangela
Esposito, Sabrina
Pedone, Paolo Vincenzo
Ciardiello, Fortunato
Troiani, Teresa
Chambery, Angela
author_sort Russo, Rosita
collection PubMed
description Background: The clinical impact of the monoclonal antibody cetuximab targeting the EGFR in colorectal cancer (CRC) is widely recognized. Nevertheless, the onset of cetuximab resistance is a serious issue that limits the effectiveness of this drug in targeted therapies. Unraveling the molecular players involved in cancer resistance is the first step towards the identification of alternative signaling pathways that can be targeted to circumvent resistance mechanisms restoring the efficacy of therapeutic treatments in a tailored manner. Methods: By applying a nanoLC-MS/MS TMT isobaric labeling-based approach, we have delineated a molecular hallmark of cetuximab-resistance in CRC. Results: We identified macrophage migration inhibitory factor (MIF) as a molecular determinant capable of triggering cancer resistance in sensitive human CRC cells. Blocking the MIF axis in resistant cells by a selective MIF inhibitor restores cell sensitivity to cetuximab. The combined treatment with cetuximab and the MIF inhibitor further enhanced cell growth inhibition in CRC resistant cell lines with a synergistic effect depending on inhibition of key downstream effectors of the MAPK and AKT signaling pathways. Conclusions: Collectively, our results suggest the association of MIF signaling and its dysregulation to cetuximab drug resistance, paving the way to the development of personalized combination therapies targeting the MIF axis.
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spelling pubmed-68264022019-11-18 Macrophage Migration Inhibitory Factor Is a Molecular Determinant of the Anti-EGFR Monoclonal Antibody Cetuximab Resistance in Human Colorectal Cancer Cells Russo, Rosita Matrone, Nunzia Belli, Valentina Ciardiello, Davide Valletta, Mariangela Esposito, Sabrina Pedone, Paolo Vincenzo Ciardiello, Fortunato Troiani, Teresa Chambery, Angela Cancers (Basel) Article Background: The clinical impact of the monoclonal antibody cetuximab targeting the EGFR in colorectal cancer (CRC) is widely recognized. Nevertheless, the onset of cetuximab resistance is a serious issue that limits the effectiveness of this drug in targeted therapies. Unraveling the molecular players involved in cancer resistance is the first step towards the identification of alternative signaling pathways that can be targeted to circumvent resistance mechanisms restoring the efficacy of therapeutic treatments in a tailored manner. Methods: By applying a nanoLC-MS/MS TMT isobaric labeling-based approach, we have delineated a molecular hallmark of cetuximab-resistance in CRC. Results: We identified macrophage migration inhibitory factor (MIF) as a molecular determinant capable of triggering cancer resistance in sensitive human CRC cells. Blocking the MIF axis in resistant cells by a selective MIF inhibitor restores cell sensitivity to cetuximab. The combined treatment with cetuximab and the MIF inhibitor further enhanced cell growth inhibition in CRC resistant cell lines with a synergistic effect depending on inhibition of key downstream effectors of the MAPK and AKT signaling pathways. Conclusions: Collectively, our results suggest the association of MIF signaling and its dysregulation to cetuximab drug resistance, paving the way to the development of personalized combination therapies targeting the MIF axis. MDPI 2019-09-25 /pmc/articles/PMC6826402/ /pubmed/31557914 http://dx.doi.org/10.3390/cancers11101430 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Russo, Rosita
Matrone, Nunzia
Belli, Valentina
Ciardiello, Davide
Valletta, Mariangela
Esposito, Sabrina
Pedone, Paolo Vincenzo
Ciardiello, Fortunato
Troiani, Teresa
Chambery, Angela
Macrophage Migration Inhibitory Factor Is a Molecular Determinant of the Anti-EGFR Monoclonal Antibody Cetuximab Resistance in Human Colorectal Cancer Cells
title Macrophage Migration Inhibitory Factor Is a Molecular Determinant of the Anti-EGFR Monoclonal Antibody Cetuximab Resistance in Human Colorectal Cancer Cells
title_full Macrophage Migration Inhibitory Factor Is a Molecular Determinant of the Anti-EGFR Monoclonal Antibody Cetuximab Resistance in Human Colorectal Cancer Cells
title_fullStr Macrophage Migration Inhibitory Factor Is a Molecular Determinant of the Anti-EGFR Monoclonal Antibody Cetuximab Resistance in Human Colorectal Cancer Cells
title_full_unstemmed Macrophage Migration Inhibitory Factor Is a Molecular Determinant of the Anti-EGFR Monoclonal Antibody Cetuximab Resistance in Human Colorectal Cancer Cells
title_short Macrophage Migration Inhibitory Factor Is a Molecular Determinant of the Anti-EGFR Monoclonal Antibody Cetuximab Resistance in Human Colorectal Cancer Cells
title_sort macrophage migration inhibitory factor is a molecular determinant of the anti-egfr monoclonal antibody cetuximab resistance in human colorectal cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826402/
https://www.ncbi.nlm.nih.gov/pubmed/31557914
http://dx.doi.org/10.3390/cancers11101430
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