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 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 Ser50 and Ser378. 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.