Investigating mammalian target of rapamycin inhibitors for their anticancer properties

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Abstract
The mammalian target of rapamycin (mTOR) is a key element of the PI3KAkt (protein kinase B) signalling pathway, responsible for the regulation of cell growth and proliferation. There are two main downstream messengers of the mTOR kinase, eukaryotic initiation factor 4E-binding protein-1 and the 40S ribosomal protein S6 kinase 1, that control translation and cell-cycle progression. Abnormal activation of the mTOR pathway occurs frequently in numerous human malignancies; therefore, mTOR represents an attractive target for anticancer drug development. Rapamycin and its analogues CCI-779, RAD-001 and AP-23573 are known specific inhibitors of the mTOR kinase. Several clinical Phase I/II trials showed their activity in solid tumours and haematological malignancies. Moreover, inhibitors of mTOR were found to synergise with some cytostatics or other biological agents, which seems to be a promising direction for future strategies of antitumour treatment.