Metastatic
colorectal cancer (CRC) is incurable for most patients. Since
mammalian target of rapamycin (mTOR) has been suggested as a crucial modulator of
tumor biology, we aimed at evaluating the effectiveness of mTOR targeting for CRC
therapy. To this purpose, we analyzed mTOR expression and the effect of mTOR inhibition in
cancer stem-like cells isolated from three human metastatic
CRCs (CoCSCs). CoCSCs exhibited a strong mTOR complex 2 (
mTORC2) expression, and a rare expression of mTOR complex 1 (
mTORC1). This latter correlated with differentiation, being expressed in CoCSC-derived xenografts. We indicate
Serum/glucocorticoid-regulated kinase 1 (SGK1) as the possible main
mTORC2 effector in CoCSCs, as highlighted by the negative effect on
cancer properties following its knockdown.
mTOR inhibitors affected CoCSCs differently, resulting in proliferation, autophagy as well as apoptosis induction. The apoptosis-inducing mTOR inhibitor Torin-1 hindered growth, motility, invasion, and survival of CoCSCs in vitro, and suppressed
tumor growth in vivo with a concomitant reduction in vessel formation. Torin-1 also affected the expression of markers for cell proliferation, angio-/lympho-genesis, and stemness in vivo, including Ki67, DLL1, DLL4, Notch, Lgr5, and CD44. Importantly, Torin-1 did not affect the survival of normal colon stem cells in vivo, suggesting its selectivity towards
cancer cells. Thus, we propose Torin-1 as a powerful
drug candidate for metastatic CRC
therapy.