AZD6244 (ARRY‐142886) enhances the antitumor activity of rapamycin in mouse models of human hepatocellular carcinoma
Open Access
- 25 January 2010
- Vol. 116 (5), 1315-1325
- https://doi.org/10.1002/cncr.24863
Abstract
BACKGROUND: The protein kinase B (AKT)/mammalian target of rapamycin (AKT/mTOR) and mitogen activated protein kinase/extracellular regulated kinase kinase/extracellular regulated kinase (MEK/ERK) signaling pathways have been shown to play an important role in hepatocellular carcinoma (HCC) growth and angiogenesis, suggesting that inhibition of these pathways may have therapeutic potential. METHODS: We treated patient-derived HCC xenografts with 1) mTOR inhibitor rapamycin (RAPA); 2) MEK inhibitor AZD6244 (ARRY-142886); and 3) AZD6244 plus RAPA (AZD6244/RAPA). Western blotting was used to determine pharmacodynamic changes in biomarkers relevant to angiogenesis, mTOR pathway, and MEK signaling. Apoptosis, microvessel density, and cell proliferation were analyzed by immunohistochemistry. RESULTS: We report here that pharmacological inhibition of the MEK/ERK pathway by AZD6244 enhanced the antitumor and antiangiogenic activities of mTOR inhibitor RAPA in both orthotopic and ectopic models of HCC. Such inhibition led to increased apoptosis, decreased angiogenesis and cell proliferation, reduced expression of positive cell cycle regulators, and increase in proapoptotic protein Bim. CONCLUSIONS: Our findings indicate that the AZD6244/RAPA combination had antitumor and antiangiogenic effects in preclinical models of human HCC. Given the urgent need for effective therapies in HCC, clinical evaluating AZD6244/RAPA combination seems warranted. Cancer 2010. © 2010 American Cancer Society.Keywords
This publication has 42 references indexed in Scilit:
- RAD001 (everolimus) inhibits tumour growth in xenograft models of human hepatocellular carcinomaJournal of Cellular and Molecular Medicine, 2009
- Tumor Recovery by Angiogenic Switch from Sprouting to Intussusceptive Angiogenesis after Treatment with PTK787/ZK222584 or Ionizing RadiationThe American Journal of Pathology, 2008
- Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse modelJCI Insight, 2008
- Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancerJCI Insight, 2008
- Development of sorafenib and other molecularly targeted agents in hepatocellular carcinomaCancer, 2007
- PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTORJCI Insight, 2007
- Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinomaMolecular Cancer Therapeutics, 2007
- “Of mice and men”European Journal Of Cancer, 2004
- Marked Induction of the IAP Family Antiapoptotic Proteins Survivin and XIAP by VEGF in Vascular Endothelial CellsBiochemical and Biophysical Research Communications, 1999
- Recurrence of hepatocellular carcinoma after surgeryBritish Journal of Surgery, 1996