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Targeting MEK with PD325901 Inhibits Hepatocellular Carcinoma Growth in TGF-α Transgenic Mice
Matthew Hennig1, Patrick Klein1,2, Navin Bansal3, Nedumangalam Hekmatyar3, Sabrina Wentz1, Amanda Norris1, Stephen Noble1, Courtney Doyle1, Huangbing Wu1, Yufang Wang1, Jean Campbell4, Nelson Fausto4, Glenn Merlino6, Judith Sebolt-Leopold7, C M. Schmidt1,8; 1Surgery, Indiana University , Indianapolis, IN; 2Pharmacology and Toxicology, Indiana University, Indianapolis, IN; 3Radiology, Indiana University, Indianapolis, IN; 4Pathology, University of Washington, Seattle, WA; 5Biology, University of North Carolina-Charlotte, Charlotte, NC; 6Molecular Genetics, National Institutes of Health, Bethesda, MD; 7Pfizer Global R&D, Inc., Ann Arbor, MI; 8Richard L. Roudebush VAMC, Indianapolis, IN

Background: Hepatocellular carcinoma (HCC) is a common cause of death from solid organ malignancy worldwide. Systemic chemotherapy has been largely unsuccessful; thus, novel treatments are needed. Extracellular-regulated kinase kinase (MEK) signaling is a critical growth regulatory pathway in HCC. Targeting MEK with a novel small molecule inhibitor, PD325901, may inhibit HCC tumorigenesis. Methods: MT-42 (CD-1) TGF-α transgenic mice spontaneously form HCC, a process accelerated with diethylnitrosamine (5 mg/kg i.p.) at 2 weeks of age. Hepatocytes (TAMH) isolated from the livers of TGF-α transgenic mice grow aggressively in culture and form flank HCC tumors in athymic nude mice. ERK expression was determined by Western blot. MEK activity was determined by phospho-specific ERK immunoblot. Cell growth was determined by trypan-blue excluded cell counts. Tumor growth was determined by caliper measurement or volumetric averaging by magnetic resonance imaging (MRI). Results: PD325901 (0.01-100 nM) inhibited MEK activity in TAMH cells in a concentration-dependent fashion at 1 hr and 24 hr time points. PD325901 treatment also resulted in a concentration-dependent inhibition in cell growth (48 hr IC50 = 0.1 nM). Athymic mice bearing TAMH flank tumors >100 mm3 were treated with vehicle or PD325901 (20 mg/kg; once daily; gavage) for 24 hrs or 16 days. Ex vivo analysis revealed a significant reduction of MEK activity (average 54%, n=10, p<0.01) in TAMH tumors at 24 hours after a single dose of PD325901. Growth rate of flank tumors over the 16 days was reduced 3 fold in the treatment arm (1113 ± 269 % v 3077 ± 483 %, P < 0.01). To confirm this in our developmental model, 37 MT-42 (CD-1) TGF-α mice (DEN) at 9 months of age were treated with either vehicle or PD325901 (20 mg/kg; gavage) for 5 weeks. Forty-seven percent of mice sacrificed on vehicle had gross HCC whereas only 14% had HCC in the treatment arm. Separately, MT-42 (CD-1) TGF-α mice (DEN) underwent screening magnetic resonance imaging (MRI) to detect HCC at >6 months of life. Two mice with index lesions (HCC) underwent determination of baseline tumor growth with volumetric averaging by bi-weekly MRI, followed by treatment with PD325901. Volumetric determinations demonstrated an average 43% decrease in tumor growth with PD325901 relative to vehicle. Conclusions: These studies demonstrate that targeting MEK with PD325901 decreases experimental HCC growth in vitro and in vivo. This provides compelling preclinical evidence that targeting MEK in human clinical trials may be promising in the treatment of HCC.


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