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

// Juliette Sauveur 1 , Eva-Laure Matera 1 , Kamel Chettab 1 , Philippe Valet 2 , Jerome Guitton 3, 4 , Ariel Savina 5 and Charles Dumontet 1, 6 1 Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS 5286 University of Lyon, Lyon, France 2 Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Université de Toulouse, UPS, Toulouse, France 3 Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Laboratoire de Biochimie-toxicologie, Pierre Bénite, France 4 Université Lyon, ISPBL, Faculté de Pharmacie, Laboratoire de Toxicologie, Lyon, France 5 Institut Roche, Paris, France 6 Hospices Civils de Lyon, Pierre Bénite, France Corrospondence to: Charles Dumontet, email: charles.dumontet@chu-lyon.fr Keywords: esophageal cancer; HER2; T-DM1; resistance; focal adhesions Received: September 08, 2017 Accepted: March 12, 2018 Published: April 20, 2018 ABSTRACT 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 E 2 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.