Targeting MEK is Effective Chemoprevention of Hepatocellular Carcinoma in TGF-α-Transgenic Mice

Abstract

Hepatocellular carcinoma (HCC) causes 600,000 mortalities per year worldwide. Previous studies from our lab provide evidence for altered mitogen-activated protein kinase and extracellular signal-regulated kinase kinase (MEK) signaling in HCC pathogenesis. We hypothesized that pharmacologic targeting of MEK may prevent HCC. Transforming growth factor-alpha-transgenic mice (CD1-MT42) exposed to diethylnitrosamine were randomized to 20 (trial I) or 35 (trial II) weeks of MEK inhibitor PD0325901 (1, 10 mg/kg) or control via orogastric gavage. Ten HCC (44%) formed in trial I controls versus 0 in treatment arms (p<0.05). Fourteen HCC (50%) formed in trial II controls versus 1 (9%) in treatment arms (p<0.05). Mean HCC volume was 578 mm3 in control versus 46 mm3 in the single tumor formed in trial II. In trial I, foci of altered hepatocytes (FAH) formed in 78% of control versus 40% and 0% (1 and 10 mg/kg PD0325901) in treatment arms (p<0.05). In trial II, incidence of FAH was 80% in control versus 20% and 50% (1 and 10 mg/kg PD0325901) in treatment arms (p<0.05). Hepatocyte expression of phosphorylated extracellular signal-regulated kinase dose-dependently decreased in trial I but remained the same in trial II. Control and treated HCC demonstrated similar proliferation rates, but apoptosis appeared increased with treatment. MEK targeting is effective HCC chemoprevention, perhaps by lowering the apoptotic threshold.

Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Inhibitors: Rationale and Importance to Inhibiting These Pathways in Human Health

“…There are few current effective therapies for HCC [36-39]. Hence targeting signaling pathways activated in HCC has been considered an approach to target HCC.…”

“…Huynh et al recently reported that treatment of human HCC xenografts with Selumetinib blocked ERK1/2 activation, reduced in vivo tumor growth, and induced apoptosis [9]. Moreover, targeting MEK with PD-0325901 had in vivo chemopreventive effects on HCC development in an animal model employing TGF-α-transgenic mice in which liver cancers were induced by diethylnitrosamine treatment [39]. Therefore, MEK represents a potential therapeutic target for HCC.…”

Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome–associated Sos1 mutation

“…PD0325901 selectively binds to and inhibits MEK, resulting in reduction of the phosphorylation and activation of Erk1/2 (19,(34)(35)(36). PD0325901 was shown to be efficient in preventing tumor incidence and growth in mice at a dosage of 1 mg/kg of body weight (mg/kg) (37). Therefore, we administered PD0325901 (1 mg/kg) daily i.p.…”

Synergistic growth inhibition of anaplastic large cell lymphoma cells by combining cellular ALK gene silencing and a low dose of the kinase inhibitor U0126

“…To block the ERK1/2 pathway we used the kinase inhibitor U0126, which is specific for MEK1/2, an upstream kinase of ERK1/2. MEK1/2 inhibitors inhibit in vitro growth of leukemic cells (Milella et al, 2001), development of human tumors in mouse xenografts (Horiuchi et al, 2003; Dai et al, 2008; Wentz et al, 2008), and are being tested in clinical trials for a variety of malignancies (Rinehart et al, 2004; Lorusso et al, 2005; Adjei et al, 2008). Interestingly, exposure of cells to U0126 significantly enhanced ALK gene silencing-induced inhibition of ALCL cell growth even at concentrations that showed little to no effect when used alone (Figure 3 and Figure 4).…”