An mTOR feedback loop mediates the ‘flare’ (‘rebound’) response to MET tyrosine kinase inhibition

Targeted therapy significantly impairs tumour growth but suffers from limitations, among which the ‘flare’ (‘rebound’) effect. Among cancers driven by tyrosine kinase receptors, those relying on alterations of the MET oncogene benefit from treatment by specific inhibitors. Previously, we reported th...

Full description

Saved in:
Bibliographic Details
Published in:Scientific reports 2023-01, Vol.13 (1), p.1378-1378, Article 1378
Main Authors: Altintas, D. M., Cerqua, M., De Laurentiis, A., Trusolino, L., Boccaccio, C., Comoglio, P. M.
Format: Article
Language:English
Subjects:
631/67/1059
631/67/395
AKT protein
c-Met protein
Cell Line, Tumor
Cell proliferation
Feedback
Feedback, Physiological
Humanities and Social Sciences
Humans
Inactivation
Kinases
Molecular modelling
multidisciplinary
Neoplasms - drug therapy
Patients
Phosphorylation
Protein-tyrosine kinase receptors
Protein-tyrosine-phosphatase
Proto-Oncogene Proteins c-akt - metabolism
Proto-Oncogene Proteins c-met - antagonists & inhibitors
Science
Science (multidisciplinary)
TOR protein
TOR Serine-Threonine Kinases - metabolism
Tumors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Targeted therapy significantly impairs tumour growth but suffers from limitations, among which the ‘flare’ (‘rebound’) effect. Among cancers driven by tyrosine kinase receptors, those relying on alterations of the MET oncogene benefit from treatment by specific inhibitors. Previously, we reported that discontinuation of MET tyrosine kinase receptor inhibition causes ‘rebound’ activation of the oncogene, with a post-treatment transient hyperphosphorylation phase that culminates into a dramatic increase in cancer cell proliferation. The molecular mechanisms behind the ‘MET burst’ after treatment cessation are unknown but critically important for patients. Here we identify a positive feedback loop mediated by the AKT/mTOR pathway leading to (a) enhanced MET translation by activating p70S6K and 4EBP1 and (b) MET hyper-phosphorylation by inactivation of the tyrosine-phosphatase PTP1B. The latter effect is due to m-TOR-driven PTP1B phosphorylation of the inhibitory residues Ser 50 and Ser 378 . These data provide in vitro evidence for the use of mTOR inhibitors to prevent the ’flare effect’ in MET targeted therapy, with potential applicative ramifications for patient clinical management.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-023-28648-3