Oncotarget

Research Papers:

Overcoming melanoma resistance to vemurafenib by targeting CCL2-induced miR-34a, miR-100 and miR-125b

Elisabetta Vergani, Lorenza Di Guardo, Matteo Dugo, Sara Rigoletto, Gabrina Tragni, Roberta Ruggeri, Federica Perrone, Elena Tamborini, Annunziata Gloghini, Flavio Arienti, Barbara Vergani, Paola Deho, Loris De Cecco, Viviana Vallacchi, Paola Frati, Eriomina Shahaj, Antonello Villa, Mario Santinami, Filippo De Braud, Licia Rivoltini and Monica Rodolfo _

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Oncotarget. 2016; 7:4428-4441. https://doi.org/10.18632/oncotarget.6599

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Abstract

Elisabetta Vergani1,*, Lorenza Di Guardo2,*, Matteo Dugo3,*, Sara Rigoletto1, Gabrina Tragni4, Roberta Ruggeri5, Federica Perrone4, Elena Tamborini4, Annunziata Gloghini4, Flavio Arienti6, Barbara Vergani7, Paola Deho1, Loris De Cecco3, Viviana Vallacchi1, Paola Frati1, Eriomina Shahaj1, Antonello Villa7, Mario Santinami5, Filippo De Braud2, Licia Rivoltini1, Monica Rodolfo1

1Immunotherapy Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

2Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

3Functional Genomics and Bioinformatics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

4Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

5Melanoma and Sarcoma Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

6Immunohematology and Transfusion Medicine Service, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

7Consorzio MIA, Microscopy and Image Analysis, University of Milan Bicocca, Monza, Italy

*These authors have contributed equally to this work

Correspondence to:

Monica Rodolfo, e-mail: monica.rodolfo@istitutotumori.mi.it

Keywords: melanoma, BRAF inhibitor, CCL2, drug resistance, miRNAs

Received: June 22, 2015    Accepted: November 25, 2015    Published: December 14, 2015

ABSTRACT

In melanoma, the adaptative cell response to BRAF inhibitors includes altered patterns of cytokine production contributing to tumor progression and drug resistance. Among the factors produced by PLX4032-resistant melanoma cell lines, CCL2 was higher compared to the sensitive parental cell lines and increased upon drug treatment. CCL2 acted as an autocrine growth factor for melanoma cells, stimulating the proliferation and resistance to apoptosis. In patients, CCL2 is detected in melanoma cells in tumors and in plasma at levels that correlate with tumor burden and lactate dehydrogenase. Vemurafenib treatment increased the CCL2 levels in plasma, whereas the long-term clinical response was associated with low CCL2 levels.

Increased CCL2 production was associated with miRNA deregulation in the resistant cells. miR-34a, miR-100 and miR-125b showed high expression in both resistant cells and in tumor biopsies that were obtained from treated patients, and they were involved in the control of cell proliferation and apoptosis. Inhibition of CCL2 and of the selected miRNAs restored both the cell apoptosis and the drug efficacy in resistant melanoma cells. Therefore, CCL2 and miRNAs are potential prognostic factors and attractive targets for counteracting treatment resistance in metastatic melanoma.


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