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Open AccessArticle

Her2-Targeted Therapy Induces Autophagy in Esophageal Adenocarcinoma Cells

1
Institute of Pathology, University of Bern, Murtenstrasse 31, 3008 Bern, Switzerland
2
Graduate School for Cellular and Biomedical Sciences, University of Bern, Freiestr. 1, 3012 Bern, Switzerland
3
Department of Visceral Surgery and Medicine, University Hospital Bern, 3010 Bern, Switzerland
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(10), 3069; https://doi.org/10.3390/ijms19103069
Received: 15 September 2018 / Revised: 4 October 2018 / Accepted: 4 October 2018 / Published: 8 October 2018
Esophageal adenocarcinoma (EAC) is a highly lethal cancer type with an overall poor survival rate. Twenty to thirty percent of EAC overexpress the human epidermal growth factor receptor 2 (Her2), a transmembrane receptor tyrosine kinase promoting cell growth and proliferation. Patients with Her2 overexpressing breast and gastroesophageal cancer may benefit from Her2 inhibitors. Therapy resistance, however, is well documented. Since autophagy, a lysosome-dependent catabolic process, is implicated in cancer resistance mechanisms, we tested whether autophagy modulation influences Her2 inhibitor sensitivity in EAC. Her2-positive OE19 EAC cells showed an induction in autophagic flux upon treatment with the small molecule Her2 inhibitor Lapatinib. Newly generated Lapatinib-resistant OE19 (OE19 LR) cells showed increased basal autophagic flux compared to parental OE19 (OE19 P) cells. Based on these results, we tested if combining Lapatinib with autophagy inhibitors might be beneficial. OE19 P showed significantly reduced cell viability upon double treatment, while OE19 LR were already sensitive to autophagy inhibition alone. Additionally, Her2 status and autophagy marker expression (LC3B and p62) were investigated in a treatment-naïve EAC patient cohort (n = 112) using immunohistochemistry. Here, no significant correlation between Her2 status and expression of LC3B and p62 was found. Our data show that resistance to Her2-directed therapy is associated with a higher basal autophagy level, which is not per se associated with Her2 status. Therefore, we propose that autophagy may contribute to acquired resistance to Her2-targeted therapy in EAC, and that combining Her2 and autophagy inhibition might be beneficial for EAC patients. View Full-Text
Keywords: autophagy; Her2; Lapatinib; LC3B; p62; OE19; Her2 inhibitor; resistance; esophageal adenocarcinoma autophagy; Her2; Lapatinib; LC3B; p62; OE19; Her2 inhibitor; resistance; esophageal adenocarcinoma
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Janser, F.A.; Adams, O.; Bütler, V.; Schläfli, A.M.; Dislich, B.; Seiler, C.A.; Kröll, D.; Langer, R.; Tschan, M.P. Her2-Targeted Therapy Induces Autophagy in Esophageal Adenocarcinoma Cells. Int. J. Mol. Sci. 2018, 19, 3069.

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