Autophagy inhibition improves sunitinib efficacy in pancreatic neuroendocrine tumors via a lysosome-dependent mechanism.

Wiedmer, Tabea; Blank, Annika; Pantasis, Sophia; Normand, Lea Elena Haaning; Bill, Ruben; Krebs, Philippe; Tschan, Mario; Marinoni, Ilaria; Perren, Aurel (2017). Autophagy inhibition improves sunitinib efficacy in pancreatic neuroendocrine tumors via a lysosome-dependent mechanism. Molecular cancer therapeutics, 16(11), pp. 2502-2515. American Association for Cancer Research AACR 10.1158/1535-7163.MCT-17-0136

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Increasing the efficacy of approved systemic treatments in metastasized pancreatic neuroendocrine tumors (PanNETs) is an unmet medical need. The anti-angiogenic tyrosine kinase inhibitor sunitinib is approved for PanNET treatment. Additionally, sunitinib is a lysosomotropic drug and such drugs can induce lysosomal membrane permeabilization as well as autophagy. We investigated sunitinib-induced autophagy as a possible mechanism of PanNET therapy resistance. Sunitinib accumulated in lysosomes and induced autophagy in PanNET cell lines. Adding the autophagy inhibitor chloroquine reduced cell viability in cell lines and in primary cells isolated from PanNET patients. The same treatment combination reduced tumor burden in the Rip1Tag2 transgenic PanNET mouse model. The combination of sunitinib and chloroquine reduced recovery and induced apoptosis in vitro, whereas single treatments did not. Knockdown of key autophagy proteins in combination with sunitinib showed similar effect as chloroquine. Sunitinib also induced lysosomal membrane permeabilization, which further increased in the presence of chloroquine or knockdown of lysosome-associated membrane protein (LAMP2). Both combinations led to cell death. Our data indicate that chloroquine increases sunitinib efficacy in PanNET treatment via autophagy inhibition and lysosomal membrane permeabilization. We suggest that adding chloroquine to sunitinib treatment will increase efficacy of PanNET treatment and that such patients should be included in respective ongoing clinical trials.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy
04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Immunopathology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Tumour Pathology

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Wiedmer, Tabea; Blank, Annika; Pantasis, Sophia; Normand, Lea Elena Haaning; Bill, Ruben; Krebs, Philippe; Tschan, Mario; Marinoni, Ilaria and Perren, Aurel

Subjects:

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

ISSN:

1535-7163

Publisher:

American Association for Cancer Research AACR

Language:

English

Submitter:

Mario Tschan

Date Deposited:

16 Oct 2017 16:48

Last Modified:

01 Nov 2018 02:33

Publisher DOI:

10.1158/1535-7163.MCT-17-0136

PubMed ID:

28729403

BORIS DOI:

10.7892/boris.105299

URI:

https://boris.unibe.ch/id/eprint/105299

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