Hypoxia leads to decreased autophosphorylation of the MET receptor but promotes its resistance to tyrosine kinase inhibitors.

Oncotarget 2018 Jun 5;9(43):27039-27058. Epub 2018 Jun 5.

University Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Target Therapies, F-59000 Lille, France.

The receptor tyrosine kinase MET and its ligand, the Hepatocyte Growth Factor/Scattor Factor (HGF/SF), are essential to the migration, morphogenesis, and survival of epithelial cells. In addition, dysregulation of MET signaling has been shown to promote tumor progression and invasion in many cancers. Therefore, HGF/SF and MET are major targets for chemotherapies. Improvement of targeted therapies requires a perfect understanding of tumor microenvironment that strongly modifies half-life, bio-accessibility and thus, efficacy of treatments. In particular, hypoxia is a crucial microenvironmental phenomenon promoting invasion and resistance to treatments. Under hypoxia, MET auto-phosphorylation resulting from ligand stimulation or from receptor overexpression is drastically decreased within minutes of oxygen deprivation but is quickly reversible upon return to normoxia. Besides a decreased phosphorylation of its proximal adaptor GAB1 under hypoxia, activation of the downstream kinases Erk and Akt is maintained, while still being dependent on MET receptor. Consistently, several cellular responses induced by HGF/SF, including motility, morphogenesis, and survival are effectively induced under hypoxia. Interestingly, using a semi-synthetic ligand, we show that HGF/SF binding to MET is strongly impaired during hypoxia but can be quickly restored upon reoxygenation. Finally, we show that two MET-targeting tyrosine kinase inhibitors (TKIs) are less efficient on MET signalling under hypoxia. Like MET loss of phosphorylation, this hypoxia-induced resistance to TKIs is reversible under normoxia. Thus, although hypoxia does not affect downstream signaling or cellular responses induced by MET, it causes immediate resistance to TKIs. These results may prove useful when designing and evaluation of MET-targeted therapies against cancer.

Download full-text PDF

Source
http://www.oncotarget.com/fulltext/25472
Publisher Site
http://dx.doi.org/10.18632/oncotarget.25472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007473PMC
June 2018
4 Reads

Publication Analysis

Top Keywords

tyrosine kinase
12
met
10
responses induced
8
cellular responses
8
treatments hypoxia
8
kinase inhibitors
8
met receptor
8
hypoxia met
8
hypoxia
8
resistance tkis
8
morphogenesis survival
8
met auto-phosphorylation
4
auto-phosphorylation ligand
4
tkis efficient
4
minutes oxygen
4
invasion resistance
4
resistance treatments
4
inhibitors tkis
4
ligand stimulation
4
stimulation receptor
4

Similar Publications