Abstract
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-α) transgenic hepatocyte (TAMH) cells, derived from the livers of TGF-α 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-αmice 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 targetingMEKin human clinical trials may be promising for the treatment of HCC.
| Original language | English |
|---|---|
| Pages (from-to) | 1218-1225 |
| Number of pages | 8 |
| Journal | Hepatology |
| Volume | 51 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2010 |
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ASJC Scopus subject areas
- Hepatology
Cite this
Targeting mitogen-activated protein Kinase Kinase with the inhibitor pd0325901 decreases hepatocellular carcinoma growth in vitro and in mouse model systems. / Hennig, Matthew; Yip-Schneider, Michele; Wentz, Sabrina; Wu, Huangbing; Hekmatyar, S. K.; Klein, Patrick; Bansal, Navin; Schmidt, C.
In: Hepatology, Vol. 51, No. 4, 04.2010, p. 1218-1225.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Targeting mitogen-activated protein Kinase Kinase with the inhibitor pd0325901 decreases hepatocellular carcinoma growth in vitro and in mouse model systems
AU - Hennig, Matthew
AU - Yip-Schneider, Michele
AU - Wentz, Sabrina
AU - Wu, Huangbing
AU - Hekmatyar, S. K.
AU - Klein, Patrick
AU - Bansal, Navin
AU - Schmidt, C.
PY - 2010/4
Y1 - 2010/4
N2 - 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-α) transgenic hepatocyte (TAMH) cells, derived from the livers of TGF-α 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-αmice 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 targetingMEKin human clinical trials may be promising for the treatment of HCC.
AB - 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-α) transgenic hepatocyte (TAMH) cells, derived from the livers of TGF-α 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-αmice 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 targetingMEKin human clinical trials may be promising for the treatment of HCC.
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U2 - 10.1002/hep.23470
DO - 10.1002/hep.23470
M3 - Article
VL - 51
SP - 1218
EP - 1225
JO - Hepatology
JF - Hepatology
SN - 0270-9139
IS - 4
ER -