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

ABSTRACT: 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 an

SUBMITTER: Altintas DM 

PROVIDER: S-EPMC9876934 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature