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

Oncotarget
Juliette SauveurCharles Dumontet

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-DM1-resistance may be associated with alterations of cell adhesion and the prostaglandin pathway, which might constitute novel therapeutic targets.

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Citations

May 22, 2019·Cancers·Elisabete Cruz da SilvaMaxime Lehmann
Jan 7, 2020·Médecine sciences : M/S·Alain BeckNicolas Joubert
Dec 17, 2019·British Journal of Cancer·Francis W HunterStephen M F Jamieson
Sep 18, 2020·Pharmaceuticals·Nicolas JoubertCaroline Denevault-Sabourin

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Methods Mentioned

BETA
flow cytometry
flow
acetylation
confocal microscopy
ELISA
PCR

Software Mentioned

ProfileXpert
GeneSpring
GraphPad Prism
Image J
RTCA
Odyssey
xCELLigence
FlowJo
Ingenuity

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