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

Rosita Russo,Davide Ciardiello,Paolo Vincenzo Pedone,Valentina Belli,Mariangela Valletta,Fortunato Ciardiello,Nunzia Matrone,Sabrina Esposito,Angela Chambery,Teresa Troiani

doi:10.3390/cancers11101430

Rosita Russo, Davide Ciardiello + Show 8 more

Open Access

https://doi.org/10.3390/cancers11101430

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Journal: Cancers	Publication Date: Sep 25, 2019
Citations: 8	License type: CC BY 4.0

Affiliation: University of Campania "Luigi Vanvitelli"

Abstract

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.

Highlights

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers and one of the leading causes of cancer-related mortality worldwide [1]
In order to delineate a hallmark of GEO/GEO-CR colon cancer cells and identify candidate proteins responsible for their cancer resistance properties, a comparative proteomic analysis was performed in cetuximab-resistant GEO cells in comparison to parental sensitive cell line
We applied a quantitative proteomic approach based on Tandem Mass Tag (TMT) isobaric labeling and nano-liquid chromatography coupled with high resolution tandem mass spectrometry

Summary

Introduction

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers and one of the leading causes of cancer-related mortality worldwide [1]. Knowledge in cancer biology has allowed developing new drugs targeting specific pathways important for carcinogenesis, metastasis, proliferation and angiogenesis with a dramatic improvement of metastatic CRC (mCRC) patients’ outcomes [2] In this scenario, epidermal growth factor receptor (EGFR) is an attractive target for anticancer therapy. Two monoclonal antibodies (mAbs) targeting the extracellular domain of the EGFR and inhibiting its activation by blocking its downstream intracellular signals (i.e., RAS-RAF-MEK-MAPK and PTEN-PIK3CA pathways) were the first targeted agents to enter the clinical setting improving the survival of mCRC patients [3,4,5]. Methods: By applying a nanoLC-MS/MS TMT isobaric labeling-based approach, we have delineated a molecular hallmark of cetuximab-resistance in CRC

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