Esophageal cancer cells resistant to T-DM1 display alterations in cell adhesion and the prostaglandin pathway
Date:
Authors:
Juliette Sauveur Eva-Laure Matera Kamel Chettab Philippe Valet Jerome Guitton Ariel Savina and Charles Dumontet
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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 E2 to T-DM1 partially restored its cytotoxic activity in resistant models. This work demonstrates that T-DM-resistance may be associated with alterations of cell adhesion and the
prostaglandin pathway, which might constitute novel therapeutic targets.
