Targeting mitogen-activated protein kinase kinase with the inhibitor PD0325901 decreases hepatocellular carcinoma growth in vitro and in mouse model systems
✍ Scribed by Matthew Hennig; Michele T. Yip-Schneider; Sabrina Wentz; Huangbing Wu; S. K. Hekmatyar; Patrick Klein; Navin Bansal; C. Max Schmidt
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- English
- Weight
- 692 KB
- Volume
- 51
- Category
- Article
- ISSN
- 0270-9139
No coin nor oath required. For personal study only.
✦ Synopsis
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-␣) transgenic hepatocyte (TAMH) cells, derived from the livers of TGF-␣ 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-␣ 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. (HEPATOLOGY 2010;51: 1218-1225.)
H epatocellular carcinoma is the most common primary liver malignancy worldwide, and its incidence has been rising over the last 20 years. 1 Surgical resection or liver transplantation is the best hope for improving survival in patients with HCC; however, only a minority of patients are candidates for these procedures. 2 Surgical resection for cure is limited to those pa-tients without distant metastases or local invasion of adjacent tissues. 3 Most patients are diagnosed with HCC at stages too advanced for curative therapy, with poor prognosis even with disease spread only to regional lymph nodes. 4 In selected patients, however, surgical resection and transplantation can achieve 5-year survival rates of approximately 60%. [5][6][7]