mTOR inhibitors are a new class of drugs whose pre-clinical effects indicate great potential as chemotherapeutics for cancer. These agents are currently in development as anti-cancer drugs and may soon become available for clinicians. mTOR inhibitors target the mammalian target of rapamycin (mTOR) protein kinase which is a downstream target of the PI3-kinase/AKT pathway. Activation of mTOR results in phosphorylation of the p70S6kinase and the 4E-BP1 translational represser, both of which are required for translation of cell cycle proteins such as D-type cyclins and c-myc. The mTOR-dependent phosphorylation of p70 induces ribosomal component biogenesis and the phosphorylation of 4E-BP1 causes its dissociation from the translation initiation factor elF-4E. Once liberated, elF-4E can participate in assembly of a functional translation initiation complex by binding to the cap structure at the 5' end of mRNAs, promoting cap-dependent translation. Rapamycin/CCI-779 inhibits this process and results in reduced levels of critical celt cycle components and G1 arrest. Tumor cells with elevated levels of AKT activity have been shown to have enhanced sensitivty to mTOR inhibitiors and we have identified several determinants of AKT-dependent sensitivity. This proposal investigates the mechanisms of AKT-dependent sensitivity and modes of intrinsic resistance of tumor cells to these compounds.
In aim 1, the proposal examines the AKT-dependent transcriptional responses of these determinants following rapamycin/CCI-779 exposure.
In aims 2 and 3 the proposal investigates the mechanisms of post-transcriptional regulation controling AKT-dependent cap-independent translation and mRNA stability of these factors. The broad objective of this proposal is understand the molecular events which regulate AKT-dependent hypersensitivity of tumor cells to these agents.
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