Tyrosine Kinase c-MET as Therapeutic Target for Radiosensitization of Head and Neck Squamous Cell Carcinomas

Abstract

The receptor tyrosine kinase c-MET activates intracellular signaling and induces cell proliferation, epithelial-to-mesenchymal-transition and migration. Within the present study, we validated the prognostic value of c-MET in patients with head and neck squamous cell carcinoma (HNSCC) treated with radio(chemo)therapy using the Cancer Genome Atlas database and found an association of increased MET gene expression and protein phosphorylation with reduced disease-specific and progression-free survival. To investigate the role of c-MET-dependent radioresistance, c-MET-positive cells were purified from established HNSCC cell lines and a reduced radiosensitivity and enhanced sphere-forming potential, compared to the c-MET-depleted cell population, was found in two out of four analyzed cell lines pointing to regulatory heterogeneity. We showed that c-MET is dynamically regulated after irradiation in vitro and in vivo. Interestingly, no direct impact of c-MET on DNA damage repair was found. The therapeutic potential of eight c-MET targeting agents in combination with irradiation demonstrated variable response rates in six HNSCC cell lines. Amongst them, crizotinib, foretinib, and Pha665752 exhibited the strongest radiosensitizing effect. Kinase activity profiling showed an association of crizotinib resistance with compensatory PI3K/AKT and MAP kinase signaling. Overall, our results indicate that c-MET is conferring radioresistance in HNSCC through modulation of intracellular kinase signaling and stem-like features.

Adaptive c-Met-PLXDC2 Signaling Axis Mediates Cancer Stem Cell Plasticity to Confer Radioresistance-associated Aggressiveness in Head and Neck Cancer

“…Our current study, using both in vitro and in vivo models, provides solid preclinical support for the potential of c-Met targeting strategies that can be used to overcome radioresistance in HNSCC. This notion was also suggested recently by a research group in Germany ( 23 ).…”

2-Hydroxy-3-methylanthraquinone inhibits homologous recombination repair in osteosarcoma through the MYC-CHK1-RAD51 axis

“…Among them, the top 20 serine/threonine protein kinases with the largest content changes were selected to investigate which kinases could phosphorylate RAD51. MET, CHK1, and c-SRC were significantly downregulated, and notably, these were related to DDR (Luttich, et al 2021 ; Bolland et al 2021 ). Next, we detected the drug sensitivities (IC 50 values) of these kinase inhibitors in the MNNG/HOS cells to identify the kinases that participate in the anti-OS effect of HMA.…”

Toward a Unifying Hypothesis for Redesigned Lipid Catabolism as a Clinical Target in Advanced, Treatment-Resistant Carcinomas

“…As noted, inhibitor studies implicate acute MET kinase signaling in maintaining the LMRS pathway [ 121 ]. Consistent with this possibility, there is substantial evidence for MET upregulation in association with advanced carcinoma treatment resistance [ 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 ]. It will be important to assess the generality of MET inhibitors in apparently suppressing LMRS metabolism in carcinomas.…”