Activated HGF-c-Met Axis in Head and Neck Cancer

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a highly morbid disease. Recent developments including Food and Drug Administration (FDA) approved molecular targeted agent's pembrolizumab and cetuximab show promise but did not improve the five-year survival which is currently less than 40%. The hepatocyte growth factor receptor; also known as mesenchymal-epithelial transition factor (c-Met) and its ligand hepatocyte growth factor (HGF) are overexpressed in head and neck squamous cell carcinoma (HNSCC); and regulates tumor progression and response to therapy. The c-Met pathway has been shown to regulate many cellular processes such as cell proliferation, invasion, and angiogenesis. The c-Met pathway is involved in cross-talk, activation, and perpetuation of other signaling pathways, curbing the cogency of a blockade molecule on a single pathway. The receptor and its ligand act on several downstream effectors including phospholipase C gamma (PLCγ), cellular Src kinase (c-Src), phosphotidylinsitol-3-OH kinase (PI3K) alpha serine/threonine-protein kinase (Akt), mitogen activate protein kinase (MAPK), and wingless-related integration site (Wnt) pathways. They are also known to cross-talk with other receptors; namely epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) and specifically contribute to treatment resistance. Clinical trials targeting the c-Met axis in HNSCC have been undertaken because of significant preclinical work demonstrating a relationship between HGF/c-Met signaling and cancer cell survival. Here we focus on HGF/c-Met impact on cellular signaling in HNSCC to potentiate tumor growth and disrupt therapeutic efficacy. Herein we summarize the current understanding of HGF/c-Met signaling and its effects on HNSCC. The intertwining of c-Met signaling with other signaling pathways provides opportunities for more robust and specific therapies, leading to better clinical outcomes.

Keywords: c-Met; head and neck squamous cell carcinoma; hepatocyte growth factor; receptor tyrosine kinase; tumor microenvironment.

Figure 1

Pro-HGF (hepatocyte growth factor) is secreted as an inactive, single-chain precursor. Activation is stimulated by wounds, chemical agents, radiation, hypoxia, and oxidative stress among other cellular disruptions. It is activated by cleavage of the bond at Arg494-Val495 by a cellular protease to yield active, heterodimeric HGF with α (consisting of four Kringle domains and a hairpin loop) and β-chains linked by a disulfide bond. Extracellularly, the c-Met receptor consist of the sema domain (with disulfide linked α-β domains), the PSI (Plexin, Semaphorin, and Integrin) domain and four IPT (Ig-like, plexins, transcription factors) domains. Intracellular mesenchymal–epithelial transition factor (c-Met) domains include a kinase domain flanked by the juxtamembrane domain and the multifunctional docking site. High affinity binding occurs between the hairpin loop and first Kringle domain of the α-chain of HGF and the third and fourth IPT domain of c-Met. Low affinity binding occurs between the β-chain of HGF and the sema domain of c-Met.

Figure 2

Hepatocyte growth factor (HGF) binding c-Met activates signaling cascades including Src, CT10 (chicken tumor virus No. 10) regulator of kinase (Crk), mitogen-activated protein kinase/ extracellular signal-regulated kinases (Mapk/Erk), and phosphotidylinsitol-3-OH kinase (PI3K), leading to loss of tumor cell apoptosis, survival, transformation, invasion, and motility. Downregulation of c-Met are highlighted in blue. c-Met signaling that promotes cell survival and apoptotic resistance are highlighted in lavender. c-Met signaling that promotes transformation is highlighted in orange. c-Met signaling that promotes invasion and motility is highlighted in green. CBL: casitas B-lineage lymphoma; FAK: focal adhesion kinase; STAT3: signal transducer and activator of transcription-3; PKC: protein kinase c; PIP3:phosphatidylinositol (3,4,5)-trisphosphate; PLC: phospholipase C; JNK: jun n-terminal kinase; Gab1: Grb2-associated adaptor protein; Grb2: growth factor receptor-bound protein 2; Akt: alpha serine/threonine-protein kinase; SOS: Ras guanine nucleotide exchange factor son-of-sevenless; Shp2: Src kinase, and Src homology region-2 containing protein tyrosine phosphatase 2; Ras: rat sarcoma; Raf: rapidly accelerated fibrosarcoma; BAD: Bcl-2 associated death promoter; p53: cellular tumor antigen p53.

Figure 3

Common c-Met mutations in head and neck squamous cell carcinoma: T230M, E168D, and N375S affect the extracellular sema domain. Intracellularly, T1010I and R988C affect the juxtamedullary (JM) domain, while Y1235D, Y1230C, T1275I, and V1333I affect the kinase domain. PSI: plexin-semaphorin-integrin domain; IPT: immunoglobulin-plexin-transcription domain; KD: kinase domain; MDF: multifunctional docking site.