Abstract
Simple SummaryThe overall five-year survival rate of patients with loco-regional advanced head and neck squamous cell carcinomas (HNSCC) is only around 40%. The curability of HNSCC with radiochemotherapy was previously found to be associated with clinical and biological parameters including tumor volume, hypoxia, epidermal growth factor receptor expression, and human papillomavirus infection status. Different signaling pathways, e.g., constitutively activated receptor tyrosine kinase signaling, increased DNA damage repair and intracellular defense against reactive oxygen species were identified as factors driving HNSCC progression and its resistance to therapy. c-MET was found to be hyperactivated in HNSCC and has been reported to drive tumor progression, therapy resistance, and metastatic spread. Here, we investigated the therapeutic potential of c-MET targeting strategies for HNSCC radiosensitization and discovered putative resistance mechanisms impeeding success of therapeutic intervention. This study highlights the importance of detailed knowledge about biological mechanisms and regulatory networks for future patient stratification and individualized treatment concepts.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.
Highlights
Every year nearly 880,000 malignant neoplasia of the head and neck region are registered worldwide and prognosis depends on tumor stage at diagnosis [1,2]
We identified altered c-MET receptor tyrosine kinase (RTK) signaling in radioresistant and stem-like population of established head and neck squamous cell carcinoma (HNSCC) cell lines, in subcutaneous xenograft model in NMRI nu/nu mice and within publicly available patient datasets (TCGA and HIPO-HNC)
According to our functional analysis, we found that MET expression negatively correlates with genes regulating DNA damage repair while it is positively associated to genes involved in cell motility, metastasis, and epithelial-mesenchymal transition (EMT) (Figure 2G)
Summary
Every year nearly 880,000 malignant neoplasia of the head and neck region are registered worldwide and prognosis depends on tumor stage at diagnosis [1,2]. Therapy resistance and uncontrolled cell growth are driven by constitutively active and oncogenic receptor tyrosine kinases (RTK) like the epidermal growth factor receptor (EGFR) and the hepatocyte growth factor (HGF) receptor c-MET (mesenchymal-epithelial transition factor) in combination with loss of function of the tumor suppressor phosphatase and tensin homolog (PTEN) leading to activation of downstream kinases such as phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) [7,8]. These genomic alterations are leading to chromosomal instability, determine tumor heterogeneity and impede therapy response. Several clinical studies, including data from our institute, demonstrated that increased MET gene expression significantly correlates with reduced locoregional control, decreased overall survival and enhanced distant metastasis after post-operative radio(chemo)therapy, especially in patients with human papillomavirus (HPV)-negative HNSCC, while it does not have prognostic potential in patients treated with primary radio(chemo)therapy [11,13,14,15,16]
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