The Raf/MEK/ERK pathway is an important mediator of
tumor cell proliferation and angiogenesis. Here, we investigated the growth-inhibitory and antiangiogenic properties of
PD0325901, a novel
MEK inhibitor, in human
melanoma cells.
PD0325901 effects were determined in a panel of
melanoma cell lines with different genetic aberrations.
PD0325901 markedly inhibited ERK phosphorylation and growth of both BRAF mutant and wild-type
melanoma cell lines, with IC(50) in the nanomolar range even in the least responsive models. Growth inhibition was observed both in vitro and in vivo in xenograft models, regardless of BRAF mutation status, and was due to G(1)-phase cell cycle arrest and subsequent induction of apoptosis. Cell cycle (
cyclin D1, c-Myc, and p27(KIP1)) and apoptosis (Bcl-2 and
survivin) regulators were modulated by
PD0325901 at the
protein level. Gene expression profiling revealed profound modulation of several genes involved in the negative control of MAPK signaling and
melanoma cell differentiation, suggesting alternative, potentially relevant mechanisms of action. Finally,
PD0325901 inhibited the production of the proangiogenic factors
vascular endothelial growth factor and
interleukin 8 at a transcriptional level. In conclusion,
PD0325901 exerts potent growth-inhibitory, proapoptotic, and antiangiogenic activity in
melanoma lines, regardless of their BRAF mutation status. Deeper understanding of the molecular mechanisms of action of
MEK inhibitors will likely translate into more effective treatment strategies for patients experiencing
malignant melanoma.