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

• 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
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-023-28648-3

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.