In this study we observed a dominant role for the HGF/MET axis in mediating resistance to BRAF and MEK inhibitors in models of BRAFV600E and NRAS mutant melanoma.
To address this question in vivo in a spontaneous melanoma model, we deleted ADAM-9 in mice carrying the hepatocyte growth factor (Hgf) transgene and knock-in mutation Cdk4<sup>R24C/R24C</sup>, demonstrated to spontaneously develop melanoma.
Higher serum/plasma HGF levels are associated with therapy resistance and/or metastasis, while lower HGF levels are associated with progression-free survival and overall survival after treatment with targeted drugs in lung cancer, gastric cancer, colon cancer, and malignant melanoma.
To determine whether hrIL-7/HGFβ has antitumor activity, we injected this hybrid cytokine into melanoma and colon cancer animal models, and then assessed the local tumor growth and tumor metastasis.
In this review, we summarize how the HGF/SF transgenic mouse has been used to reveal metastasis-regulating activity of four different genes (<i>CDK4</i><sup>R24C</sup>, <i>survivin</i> and <i>NME1/NME2</i>) in the context of UV-induced melanoma.
The aim of this study was to analyze the pharmacokinetics of vemurafenib by a population approach and to evaluate the relationship between plasma drug exposure and pre-treatment plasma hepatocyte growth factor (HGF) levels with clinical effects (progression-free survival (PFS), peripheral lymphocytes depletion) in patients with metastatic BRAF<sup>V600</sup> mutated melanoma treated with single agent vemurafenib.
These results suggest that SPINT2 is associated with tumor-suppressive functions in melanoma by inhibiting an extracellular signal regulator of HGF, which is typically activated by tumor-stromal interactions.
Consequent patient evaluation in collaboration with the Melanoma Institute Australia of a cohort of 41 melanoma specimens with extensive clinical annotation failed to validate HGF immunohistochemistry as a predictor of response to BRAF inhibitors.
However, long-term curative effect was achieved by the augmentation of the CD-MSC/5FC regimen along with the inhibition of c-Met/hepatocyte growth factor signaling axis in this aggressive melanoma derivative.
Although stimulation of melanoma N1 cells (GD3+ and GD3-) with either HGF or adhesion to CL-I did not show marked differences in the phosphorylation levels of Akt at Ser473 and Thr308 between two types of cells, simultaneous treatment resulted in definite and markedly increased activation of Akt in GD3+ cells.
Interestingly, no differences were observed in the invasive characteristics of primary melanomas of HGF(+) and HGF(+) × [m1m2](+/-) strains, with both exhibiting invasion into the dermis and subcutis, indicating factors other than simple invasive activity were responsible for metastasis of HGF(+) × [m1m2](+/-) melanomas.
In vivo, we used the HGF transgenic mouse model of UV-induced melanoma to demonstrate that topical treatment with l-selenomethionine results in a significant delay in the time required for UV-induced melanoma development, but also increases the rate of growth of those tumors once they appear.
Dual inhibition of RAF and either HGF or MET resulted in reversal of drug resistance, suggesting RAF plus HGF or MET inhibitory combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma.
Suppression of endogenous RasGRP3 expression in these melanoma cell lines reduced Ras-GTP formation as well as c-Met expression and Akt phosphorylation downstream from hepatocyte growth factor (HGF) or epidermal growth factor (EGF) stimulation.
We also showed Rap1 and ERK activation by both hepatocyte growth factor (HGF) and 8CPT-2Me-cAMP (an activator of Epac, a Rap1 guanine nucleotide exchange factor) in two human melanoma cell lines.
Finally, dominant-negative inhibition of Mitf resulted in profound resistance of melanocytes and melanoma cells to HGF-dependent matrix invasion, suggesting a physiologic role for this pathway in melanocytic development and melanoma.
Recently, we reported that hepatocyte growth factor/scatter factor (HGF/SF)-transgenic mice develop melanomas after a single erythemal dose of neonatal UV radiation, supporting epidemiological data implicating childhood sunburn in CMM.
Hepatocyte growth factor (HGF), a fibroblast-derived protein that affects the growth, motility and differentiation of epithelial cells, is a mitogen for human melanocytes and has recently been implicated as an important factor for the development and dissemination of melanomas.