Research Papers:

Esophageal cancer cells resistant to T-DM1 display alterations in cell adhesion and the prostaglandin pathway

Juliette Sauveur, Eva-Laure Matera, Kamel Chettab, Philippe Valet, Jerome Guitton, Ariel Savina and Charles Dumontet _

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Oncotarget. 2018; 9:21141-21155. https://doi.org/10.18632/oncotarget.24975

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Juliette Sauveur1, Eva-Laure Matera1, Kamel Chettab1, Philippe Valet2, Jerome Guitton3,4, Ariel Savina5 and Charles Dumontet1,6

1Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS 5286 University of Lyon, Lyon, France

2Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Université de Toulouse, UPS, Toulouse, France

3Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Laboratoire de Biochimie-toxicologie, Pierre Bénite, France

4Université Lyon, ISPBL, Faculté de Pharmacie, Laboratoire de Toxicologie, Lyon, France

5Institut Roche, Paris, France

6Hospices Civils de Lyon, Pierre Bénite, France

Corrospondence to:

Charles Dumontet, email: [email protected]

Keywords: esophageal cancer; HER2; T-DM1; resistance; focal adhesions

Received: September 08, 2017    Accepted: March 12, 2018    Published: April 20, 2018


Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate that specifically targets HER2 thanks to its antibody component trastuzumab. In spite of responses to this novel agent, acquired resistance to treatment remains a major obstacle. Prolonged in vitro exposure of the gastroesophageal junction cancer cell line OE-19 to T-DM1, in the absence or presence of ciclosporin A resulted in the selection of two resistant cell lines to T-DM1. T-DM1-resistant cells presented an increased expression of adhesion genes, altered spreading and higher sensitivity to anoikis than parental cells. A resistant cell line showed decreased adhesion strength, increased migration speed and increased sensitivity to RhoA inhibition. Genes involved in the prostaglandin pathway were deregulated in resistant models. Addition of prostaglandin E2 to T-DM1 partially restored its cytotoxic activity in resistant models. This work demonstrates that T-DM1-resistance may be associated with alterations of cell adhesion and the prostaglandin pathway, which might constitute novel therapeutic targets.

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