Simultaneous Inhibition of the HGF-MET and Erk1-2 Pathways Affect Uveal Melanoma Cell Growth and MigrationReportar como inadecuado

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Nearly all primary uveal melanoma UM that metastasize involve the liver. Hepatocyte growth factor HGF is proposed to be an important microenvironmental element in attracting-supporting UM metastasis through activation of MET. The majority >85% of UM express mutations in the G-alpha proteins, that drive the MEK-ERK1-2 pathway. Thus, we proposed that the combination of MET and MEK inhibition would inhibit the growth and migration of G-alpha protein mutant versus non-mutant UM cells.


Western-blots demonstrated the relative protein levels of ERK1-2 and MET in UM cells. Cells were treated with the small molecule inhibitors AZD6244 MEKi and-or MK-8033 METi and downstream markers evaluated. Further studies determined the effect of combination MEKi and METi treatment on cell growth, apoptosis and migration.


All G-alpha protein mutant UM cell lines express MET mRNA and protein. The level of mRNA expression correlates with protein expression. MEKi, but not METi treatment results in markedly reduced ERK1-2 phosphorylation. Either MEKi or METi treatment alone results in reduced cell proliferation, but only modest induction of apoptosis. The combination MEKi+METi results in significant reduction of proliferation in G-alpha protein mutant cells. UM cell migration was blocked by METi, but not MEKi treatment.


MET protein expression showed no correlation with G-alpha protein mutation status. Combining MEKi with METi treatment has added benefit to either treatment alone in reducing G-alpha protein mutant UM cell growth. Combining METi with MEKi treatment adds the effect of limiting uveal melanoma cell migration.

Autor: Chandrani Chattopadhyay, Elizabeth A. Grimm, Scott E. Woodman



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