Macropinocytosis renders a subset of pancreatic tumor cells resistant to mTOR inhibition

Michalopoulou, E., Auciello, F. R., Bulusu, V., Strachan, D., Campbell, A. D., Tait-Mulder, J., Karim, S. A., Morton, J. P. , Sansom, O. J. and Kamphorst, J. J. (2020) Macropinocytosis renders a subset of pancreatic tumor cells resistant to mTOR inhibition. Cell Reports, 30(8), 2729-2742.e4. (doi: 10.1016/j.celrep.2020.01.080) (PMID:32101748) (PMCID:PMC7043007)

[img]
Preview
Text
208200.pdf - Published Version
Available under License Creative Commons Attribution.

4MB

Abstract

Pancreatic ductal adenocarcinoma (PDAC) features a near-universal mutation in KRAS. Additionally, the tumor suppressor PTEN is lost in ∼10% of patients, and in mouse models, this dramatically accelerates tumor progression. While oncogenic KRAS and phosphatidylinositol 3-kinase (PI3K) cause divergent metabolic phenotypes individually, how they synergize to promote tumor metabolic alterations and dependencies remains unknown. We show that in KRAS-driven murine PDAC cells, loss of Pten strongly enhances both mTOR signaling and macropinocytosis. Protein scavenging alleviates sensitivity to mTOR inhibition by rescuing AKT phosphorylation at serine 473 and consequently cell proliferation. Combined inhibition of mTOR and lysosomal processing of internalized protein eliminates the macropinocytosis-mediated resistance. Our results indicate that mTORC2, rather than mTORC1, is an important regulator of protein scavenging and that protein-mediated resistance could explain the lack of effectiveness of mTOR inhibitors in certain genetic backgrounds. Concurrent inhibition of mTOR and protein scavenging might be a valuable therapeutic approach.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Bulusu, Dr Vinay and Tait-Mulder, Dr Jacqueline and Campbell, Mr Andrew and Strachan, Mr David and Morton, Professor Jen and Karim, Ms Saadia and Michalopoulou, Ms Evdokia and Sansom, Professor Owen and Kamphorst, Dr Jurre
Creator Roles:
Michalopoulou, E.Conceptualization, Methodology, Investigation, Writing – original draft, Writing – review and editing
Sansom, O. J.Conceptualization, Writing – review and editing, Funding acquisition, Supervision
Bulusu, V.Methodology, Investigation, Writing – review and editing, Resources
Campbell, A. D.Methodology, Writing – review and editing, Resources
Karim, S. A.Methodology, Writing – review and editing, Resources
Morton, J. P.Methodology, Writing – review and editing, Resources
Kamphorst, J. J.Methodology, Writing – original draft, Writing – review and editing, Funding acquisition, Supervision
Authors: Michalopoulou, E., Auciello, F. R., Bulusu, V., Strachan, D., Campbell, A. D., Tait-Mulder, J., Karim, S. A., Morton, J. P., Sansom, O. J., and Kamphorst, J. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cell Reports
Publisher:Elsevier (Cell Press)
ISSN:2211-1247
ISSN (Online):2211-1247
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Cell Reports 30(8): 2729-2742.e4
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
170391The effect of tumour microenvironment on the metabolism of pancreatic cancer cellsJurre KamphorstCancer Research UK (CRUK)C50242/A17728CS - Beatson Institute for Cancer Research