FTIs have been shown to inhibit the growth of human tumors in preclinical animal models and are presently in clinical trials but their mechanism of antitumor activity is unknown. The hypothesis upon which this proposal is based is that FTIs inhibit tumor growth by inducing apoptosis through inhibition of phosphatidyl inositol-3-kinase (PI3K)/AKT-mediated survival and adhesion pathways. This hypothesis will be tested through the following specific aims: 1) To determine the involvement of the AKT survival pathway in FTI-277-induced apoptosis; 2) To determine the ability of FTI-277 to disrupt PI3-kinase/AKT mediated cell survival and adhesion pathways; 3) To determine the involvement of H-ras, N-ras and K-ras in mediating activation of the PI3K/AKT survival pathways, and their implication in FTI-277-induced apoptosis, and; 4) To determine the involvement of the AKT survival pathway in FTI-277 antitumor activity in the nude mouse human tumor xenograft model. Two highly potent and selective but structurally unrelated FTIs (L-739,750 and SCH66336) will be used to confirm these findings.
| Dan, Han C; Jiang, Kun; Coppola, Domenico et al. (2004) Phosphatidylinositol-3-OH kinase/AKT and survivin pathways as critical targets for geranylgeranyltransferase I inhibitor-induced apoptosis. Oncogene 23:706-15 |
