The objective of this study was to determine whether activation of the
kinase mammalian target of rapamycin (mTOR) is associated with human
melanoma. We found moderate or strong hyperphosphorylation of
ribosomal protein S6 in 78/107
melanomas (73%). In contrast, only 3/67 benign
nevi (4%) were moderately positive, and none were strongly positive. These data indicate that mTOR activation is very strongly associated with malignant, compared to benign, melanocytic lesions. Next, we tested six
melanoma-derived cell lines for evidence of mTOR dysregulation. Five of the six lines showed persistent phosphorylation of S6 after 18 hours of serum deprivation, and four had S6 phosphorylation after 30 minutes of
amino-acid withdrawal, indicating inappropriate mTOR activation. The proliferation of three
melanoma-derived lines was blocked by the mTOR inhibitor
rapamycin, indicating that mTOR activation is a growth-promoting factor in
melanoma-derived cells. mTOR is directly activated by the small
guanosine triphosphatase Ras homolog enriched in brain (Rheb), in a farnesylation-dependent manner. Therefore, to investigate the mechanism of mTOR activation, we used the farnesyl
transferase inhibitor
FTI-277, which partially blocked the growth of three of the six
melanoma cell lines. Together, these data implicate activation of mTOR in the pathogenesis of
melanoma, and suggest that Rheb and mTOR may be targets for
melanoma therapy.