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.

Combined treatment with crizotinib and temsirolimus is an effective strategy in mantle cell lymphoma and can overcome acquired resistance to temsirolimus

“…Crizotinib, targeting RTK upstream of the mTor pathway, led to similar results. In line with our observations, different authors have already described the downregulation of Met RNA and protein levels after treatment with temsirolimus and other inhibitors targeting the PI3K/Akt/mTOR pathway 55–58 . Therefore, compensatory upregulation of Met, which is known to be a potent mediator of proliferation and cell survival via different intracellular pathways, 41 could be a rational cellular escape mechanism to mediate temsirolimus resistance.…”

“…48,51,53,54 Furthermore, the AKT/mTor-pathway was shown to control Met expression due to a positive feedback loop, indicating an important crosslink between these two components. 55 We therefore sought to further elucidate the role of Met signaling for mediating resistance to mTOR inhibition in MCL. We confirmed a significant upregulation of MET RNA and Met protein levels in the resistant phenotype.…”

“…In line with our observations, different authors have already described the downregulation of Met RNA and protein levels after treatment with temsirolimus and other inhibitors targeting the PI3K/Akt/mTOR pathway. [55][56][57][58] Therefore, compensatory upregulation of Met, which is known to be a potent mediator of proliferation and cell survival via different intracellular pathways, 41 could be a rational cellular escape mechanism to mediate temsirolimus resistance. In line with the results in Z138r, we observed extremely elevated Met protein levels in the temsirolimus resistant cell line Rec-1, whereby Met expression could not be observed in the temsirolimus sensitive MCL cell lines.…”

“…Especially Met overexpression is considered a common cellular escape mechanism mediating resistance toward several drugs, including mTOR inhibitors 48,51,53,54 . Furthermore, the AKT/mTor‐pathway was shown to control Met expression due to a positive feedback loop, indicating an important crosslink between these two components 55 . We therefore sought to further elucidate the role of Met signaling for mediating resistance to mTOR inhibition in MCL.…”

The MET Oncogene: Thirty Years of Insights into Molecular Mechanisms Driving Malignancy

“…The molecular mechanisms behind this effect remain unclear, but are critically important for patients. Recently, our laboratory identified a positive feedback loop mediated by the AKT/mTOR pathway that leads to the “MET burst” after treatment withdrawal [ 83 ]. This feedback loop enhances MET translation through activation of p70S6K and 4EBP1 and causes MET hyper-phosphorylation via inactivation of the tyrosine–phosphatase PTP1B.…”