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)
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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: | Tait-Mulder, Dr Jacqueline and Strachan, Mr David and Kamphorst, Dr Jurre and Bulusu, Dr Vinay and Morton, Professor Jen and Karim, Ms Saadia and Sansom, Professor Owen and Michalopoulou, Ms Evdokia and Campbell, Dr Andrew |
| 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 > School 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 |
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