Rapamycin-Derivatives differential inhibition of the mTOR signaling pathway in colorectal cancer

The mammalian target of rapamycin (mTOR), is a highly conserved pathway actively involved in the regulation of cell proliferation in response to growth factors / receptors signaling. This occurs through phosphoinositide-3-kinase (PI-3K) to regulate cell growth, proliferation and angiogenesis. Interestingly, the PI3K and ndash;AKT-mTOR pathway is frequently deregulated in a wide range of malignant tumors including colorectal cancer. Therefore, targeting this pathway using rapamycin and/or rapamycin-derivatives to inhibit mTOR and thereby induce G1 arrest and apoptosis, becomes recently an attractive approach to eradicate a substantial number of cancers. Although colorectal cancer pathogenesis is well documented, the mTOR pathway mechanism of action however, is not well known. Therefore, molecular characterization of mTOR signaling pathway would not only help to clarify mechanisms of regulation involved, but allow also a better selection of tumors sensitive to rapamycin-derivatives. This study will explore the mTOR signaling mechanism in colorectal cancer by subjecting cell lines to RAD001, a rapamycin-derived drug and monitor changes in key phophotyrosine residues in the downstream effectors involved in apoptosis, the BAD and Mdm2. We will use three colorectal cell lines: the SW620, resistant to apoptosis-induced drugs, the SW480 bearing a p53 mutation and the HCT116 carrying B-catenin mutation. In order to define which path is preferentially targeted in each cell line, drug-serial-dilutions will be applied to cultured cells and drug-sensitivity will be assessed using MTT assay. This will provide precious information about how cells with different aberrant pathways would differentially react to RAD001 and thus allow better discrimination of tumors sensitive to RAD001drug. Ultimately, the outcome data of this project would initiate molecular characterization of tumors prior to therapy to help understanding drug resistance issue which can be beneficial for Omani population.

The mammalian target of rapamycin (mTOR), is a highly conserved pathway actively involved in the regulation of cell proliferation in response to growth factors / receptors signaling. This occurs through phosphoinositide-3-kinase (PI-3K) to regulate cell growth, proliferation and angiogenesis. Interestingly, the PI3K and ndash;AKT-mTOR pathway is frequently deregulated in a wide range of malignant tumors including colorectal cancer. Therefore, targeting this pathway using rapamycin and/or rapamycin-derivatives to inhibit mTOR and thereby induce G1 arrest and apoptosis, becomes recently an attractive approach to eradicate a substantial number of cancers. Although colorectal cancer pathogenesis is well documented, the mTOR pathway mechanism of action however, is not well known. Therefore, molecular characterization of mTOR signaling pathway would not only help to clarify mechanisms of regulation involved, but allow also a better selection of tumors sensitive to rapamycin-derivatives. This study will explore the mTOR signaling mechanism in colorectal cancer by subjecting cell lines to RAD001, a rapamycin-derived drug and monitor changes in key phophotyrosine residues in the downstream effectors involved in apoptosis, the BAD and Mdm2. We will use three colorectal cell lines: the SW620, resistant to apoptosis-induced drugs, the SW480 bearing a p53 mutation and the HCT116 carrying B-catenin mutation. In order to define which path is preferentially targeted in each cell line, drug-serial-dilutions will be applied to cultured cells and drug-sensitivity will be assessed using MTT assay. This will provide precious information about how cells with different aberrant pathways would differentially react to RAD001 and thus allow better discrimination of tumors sensitive to RAD001drug. Ultimately, the outcome data of this project would initiate molecular characterization of tumors prior to therapy to help understanding drug resistance issue which can be beneficial for Omani population.