Her2-Targeted Therapy Induces Autophagy in Esophageal Adenocarcinoma Cells.

Janser, Félice A.; Adams, Olivia Joan; Bütler, Vanessa; Bill, Anna Magdalena; Dislich, Bastian; Seiler, Christian A.; Kröll, Dino; Langer, Rupert; Tschan, Mario (2018). Her2-Targeted Therapy Induces Autophagy in Esophageal Adenocarcinoma Cells. International journal of molecular sciences, 19(10) Molecular Diversity Preservation International MDPI 10.3390/ijms19103069

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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 ( = 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Med. Onkologie / Hämatologie (Erw.)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Med. Onkologie / Hämatologie (Erw.)

04 Faculty of Medicine > Service Sector > Institute of Pathology > Tumour Pathology

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Bill, Félice Ariane; Adams, Olivia Joan; Bill, Anna Magdalena; Dislich, Bastian; Seiler, Christian A.; Kröll, Dino; Langer, Rupert and Tschan, Mario

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1661-6596

Publisher:

Molecular Diversity Preservation International MDPI

Language:

English

Submitter:

Mario Tschan

Date Deposited:

16 Oct 2018 07:53

Last Modified:

05 Sep 2019 09:57

Publisher DOI:

10.3390/ijms19103069

PubMed ID:

30297650

Uncontrolled Keywords:

Her2 Her2 inhibitor LC3B Lapatinib OE19 autophagy esophageal adenocarcinoma p62 resistance

BORIS DOI:

10.7892/boris.120469

URI:

https://boris.unibe.ch/id/eprint/120469

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