Combined Inhibition of MEK and mTOR Signaling Inhibits Initiation and Progression of Colorectal Cancer

The role of the mTOR signal pathway in colorectal cancer (CRC) pathogenesis remains unclear, and the combination effect of PD98059 (an inhibitor for MEK) and rapamycin (an inhibitor for mTOR) on CRC is still unknown. Here, we found that combination treatment with PD98059 and rapamycin suppressed the proliferation of CRC cells, induced apoptosis, arrested cell cycle, and reduced the incidence and volume of CRC in mice, as well as inhibited phosphorylation of mTOR and the MEK signal pathway components, of which the effects were more significant than single-drug treatments. These findings indicate that PD98059 combined with rapamycin appears to be a promising strategy for inhibiting the initiation, and progression of CRC, which may provide a novel strategy for CRC prevention.

[1]  K. Flaherty,et al.  Combined inhibition of MAPK and mTOR signaling inhibits growth, induces cell death, and abrogates invasive growth of melanoma cells. , 2008, The Journal of investigative dermatology.

[2]  D. Lauffenburger,et al.  Multipathway Model Enables Prediction of Kinase Inhibitor Cross-Talk Effects on Migration of Her2-Overexpressing Mammary Epithelial Cells , 2008, Molecular Pharmacology.

[3]  R. Perez-soler,et al.  Targeting protein translation in human non small cell lung cancer via combined MEK and mammalian target of rapamycin suppression. , 2007, Cancer research.

[4]  Douglas A. Lauffenburger,et al.  Common effector processing mediates cell-specific responses to stimuli , 2007, Nature.

[5]  Wei Li,et al.  Rapamycin together with herceptin significantly increased anti‐tumor efficacy compared to either alone in ErbB2 over expressing breast cancer cells , 2007, International journal of cancer.

[6]  H. Nagawa,et al.  Phosphorylation of ribosomal p70 S6 kinase and rapamycin sensitivity in human colorectal cancer. , 2007, Cancer letters.

[7]  C. Der,et al.  Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer , 2007, Oncogene.

[8]  Jing-Yuan Fang,et al.  Inhibition of the Extracellular Signal-regulated Kinase/Mitogen-activated Protein Kinase Pathway Decreases DNA Methylation in Colon Cancer Cells* , 2007, Journal of Biological Chemistry.

[9]  T. Giordano,et al.  Mammalian target of rapamycin inhibitors as possible adjuvant therapy for microscopic residual disease in head and neck squamous cell cancer. , 2007, Cancer research.

[10]  C. Tsang,et al.  Targeting mammalian target of rapamycin (mTOR) for health and diseases. , 2007, Drug discovery today.

[11]  S. Johnston,et al.  Small Molecule Signal Transduction Inhibitors for the Treatment of Solid Tumors , 2007, Cancer investigation.

[12]  T. Veenstra,et al.  Identification of a Highly Effective Rapamycin Schedule that Markedly Reduces the Size, Multiplicity, and Phenotypic Progression of Tobacco Carcinogen–Induced Murine Lung Tumors , 2006, Clinical Cancer Research.

[13]  E. Kılıç,et al.  Human vascular endothelial growth factor protects axotomized retinal ganglion cells in vivo by activating ERK-1/2 and Akt pathways , 2006 .

[14]  P. Houghton,et al.  mTOR and cancer therapy , 2006, Oncogene.

[15]  C. Proud,et al.  When translation meets transformation: the mTOR story , 2006, Oncogene.

[16]  N. Sonenberg,et al.  mTOR, translation initiation and cancer , 2006, Oncogene.

[17]  J. Dancey.  Therapeutic targets: MTOR and related pathways , 2006, Cancer biology & therapy.

[18]  E. Raymond,et al.  New paradigms in anticancer therapy: targeting multiple signaling pathways with kinase inhibitors. , 2006, Seminars in oncology.

[19]  V. Hwa,et al.  Interferon-gamma-induced dephosphorylation of STAT3 and apoptosis are dependent on the mTOR pathway. , 2006, Experimental cell research.

[20]  Keith T Flaherty,et al.  Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases , 2006, Molecular Cancer Therapeutics.

[21]  M. Hall,et al.  TOR Signaling in Growth and Metabolism , 2006, Cell.

[22]  G. Georgakis,et al.  From Rapa Nui to rapamycin: targeting PI3K/Akt/mTOR for cancer therapy , 2006, Expert review of anticancer therapy.

[23]  N. Hay,et al.  The Akt-mTOR tango and its relevance to cancer. , 2005, Cancer cell.

[24]  Jing-Yuan Fang,et al.  The MAPK signalling pathways and colorectal cancer. , 2005, The Lancet. Oncology.

[25]  E. Petricoin,et al.  Pathology of the Future: Molecular Profiling for Targeted Therapy , 2005, Cancer investigation.

[26]  Yoshimasa Uehara,et al.  Mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitors restore anoikis sensitivity in human breast cancer cell lines with a constitutively activated extracellular-regulated kinase (ERK) pathway. , 2002, Molecular cancer therapeutics.

[27]  Yung-Hyun Choi,et al.  PD98059 triggers G1 arrest and apoptosis in human leukemic U937 cells through downregulation of Akt signal pathway. , 2007, International immunopharmacology.

[28]  M. Hidalgo,et al.  Targeting mTOR for cancer treatment. , 2006, Advances in experimental medicine and biology.

[29]  B. Vogelstein,et al.  Tumours of the colon and rectum: Carcinoma of the colon and rectum , 2000 .

[30]  Stanley R. Hamilton,et al.  Pathology and genetics of tumours of the digestive system , 2000 .