The
phosphatidylinositol 3-kinase/
protein kinase B/
mammalian target of rapamycin-pathway (PI3K/AKT/mTOR-pathway) plays a role in the regulation of cell proliferation, cell survival, angiogenesis and resistance to anti-
tumor treatments. In many
tumor types the PI3K/AKT/mTOR-pathway is found activated through several different underlying mechanisms. Since this pathway is believed to largely drive the malignant behavior of several of these
tumors, mTOR-inhibition is considered an attractive means to apply as anti-
tumor treatment. Currently, four
mTOR-inhibitors are explored for clinical use:
rapamycin,
temsirolimus (CCI-779),
everolimus (
RAD001) and
deforolimus (
AP23573). As monotherapy,
mTOR-inhibitors yield interesting anti-
tumor activity against various
tumor types at the expense of relatively mild toxicities. This recently resulted in the registration of two
mTOR-inhibitors for patients with metastatic
renal cell carcinoma (RCC) while randomized studies in other
tumors are currently in progress. Furthermore,
mTOR-inhibitors are well-suited drugs to combine with other anti-
tumor drugs as in preclinical models mTOR-inhibition overcomes chemoresistance. Consequently, mTOR-inhibitor-containing multidrug regimens are subject to clinical studies. As holds true for all anti-
tumor therapies, identification of patients who are likely to respond to mTOR-inhibitor-containing
therapies is of utmost importance to avoid over- or undertreatment. Preliminary results suggest that several factors reflecting activation of mTOR in
tumors may be used for this purpose. This review addresses the mechanism of action and current clinical experience with
mTOR-inhibitors as well as their role in overcoming resistance to conventional
therapies. Additionally, potential predictors of outcome to mTOR-inhibition are discussed.