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Targeting MEK Is Effective Chemoprevention of hepatocellular carcinoma in TGF-α Transgenic Mice
Sabrina C. Wentz*1, Huangbing Wu1, Michele T. Yip-Schneider1,2, Matthew E. Hennig1, Patrick Klein1,3, Judith Sebolt-Leopold5, C. Max Schmidt1,4
1Surgery, Indiana University School of Medicine, Indianapolis, IN; 2Indiana University Cancer Center, Indianapolis, IN; 3Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN; 4Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, IN; 5Pfizer Pharmaceuticals, Indianapolis, IN

Introduction: Hepatocellular carcinoma (HCC) yields >600,000 mortalities/year worldwide. MEK-ERK signaling has been implicated in the molecular pathogenesis of HCC. Hypothesis: MEK inhibition prevents HCC formation in a developmental animal model.
Methods: Transgenic mice overexpressing human transforming growth factor-α (TGF-α) spontaneously develop HCC, which is accelerated with diethylnitrosamine (DEN) (5mg/kg intraperitoneal x1) at age 14 days. Forty-two DEN-exposed transgenic mice were initiated on Trial I (20wks) or Trial II (35wks) at age 10 weeks. Treatment arms (n≥5/arm) were vehicle (control) or novel MEK inhibitor PD325901 (1 and 10 mg/kg) daily via orogastric lavage. Liver tissue was examined grossly and histologically for evidence of HCC, adenoma, and foci of altered hepatocytes (FAH). Proliferation and apoptosis were evaluated with Ki-67 and ApopTag® immunostains.
Results: In Trial I, 10 HCC formed in control, compared to 0 in combined treatment arms (p<0.05). HCC incidence was 44% in control compared to 0% in combined treatment arms (p<0.05). In Trial II, 14 HCC formed in control compared to 0 and 1 in 1mg/kg and 10 mg/kg treatment arms, respectively (p<0.05). HCC incidence was 50% in control compared to 0% (1mg/kg) and 20% (10mg/kg) in treatment arms (p<0.05). Mean HCC volume in control was 4474μL compared to 46μL in the 10mg/kg treatment arm. Microscopically, HCC analysis mirrored previous gross findings. In Trial I, incidences of adenoma (12%) and FAH (12%) were greater than in combined treatment arms (0%). In Trial II, incidences of adenoma (80%) and FAH (80%) were greater than in either treatment arm (40% and 20% in 1mg/kg, 33% and 67% in 10mg/kg). Apoptosis in FAH was increased in treatment arms of both trials compared to control. Ki-67 staining remained unchanged.
Conclusions: MEK inhibition with PD325901 is effective in HCC chemoprevention in a developmental animal model. The mechanism may involve lowering the apoptotic threshold of precancerous hepatocytes. This preclinical data suggests that MEK targeting is a promising method for human HCC chemoprevention.


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