Hepatocellular carcinoma (HCC) is a common cause of death from solid organ
malignancy worldwide. Extracellular signal-regulated/
mitogen-activated protein kinase kinase (
MEK) signaling is a critical growth regulatory pathway in HCC. Targeting
MEK with a novel small molecule inhibitor,
PD0325901, may inhibit HCC
tumorigenesis.
PD0325901 (0.01-100 nM) inhibited growth and
MEK activity in vitro in immortalized murine
transforming growth factor alpha (
TGF-alpha) transgenic hepatocyte (TAMH) cells, derived from the livers of
TGF-alpha transgenic mice. Treatment of athymic mice bearing TAMH flank
tumors with vehicle or
PD0325901 (20 mg/kg) revealed a significant reduction of
MEK activity ex vivo 24 hours after a single
PD0325901 dose. The growth rate of TAMH flank
tumors over 16 days was reduced threefold in the treatment arm (1113 +/- 269% versus 3077 +/- 483%, P < 0.01).
PD0325901 exhibited similar inhibitory effects in HepG2 and Hep3B human HCC cells in vitro and in Hep3B flank
tumors in vivo. To confirm this in a developmental model, MT-42 (CD-1)
TGF-alpha mice were treated with vehicle or
PD0325901 (20 mg/kg) for 5 weeks. Gross HCC was detected in 47% and 13.3% of the control and treatment mice, respectively.
Tumor growth suppression by
PD0325901 relative to vehicle was also shown by magnetic resonance imaging. These studies provide compelling preclinical evidence that targeting
MEK in human clinical trials may be promising for the treatment of HCC.