mTOR pathway in colorectal cancer: an update

Abstract

The mammalian target of rapamycin (mTOR) has emerged as a potential target for drug development, particularly due to the fact that it plays such a crucial role in cancer biology. In addition, next-generation mTOR inhibitors have become available, marking an exciting new phase in mTOR-based therapy. However, the verdict on their therapeutic effectiveness remains unclear. Here we review phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR signaling as one of the primary mechanisms for sustaining tumor outgrowth and metastasis, recent advances in the development of mTOR inhibitors, and current studies addressing mTOR activation/inhibition in colorectal cancer (CRC). We will also discuss our recent comparative study of different mTOR inhibitors in a population of colon cancer stem cells (CSCs), and current major challenges for achieving individualized drug therapy using kinase inhibitors.

Figure 1. Simplified scheme of mTOR pathway activation

Akt activation releases Rheb from the inhibitory effects of TSC1/2 thus allowing mTOR activation. Signaling defects upstream of mTOR in the PI3K/Akt/mTOR pathway (mutations in PTEN, PI3K, Akt and TSCs) lead to mTOR deregulation. Akt can also be a downstream effector of mTOR, due to mTOR association with different protein partners to form two functionally distinct signaling complexes, mTORC1 and mTORC2.

Figure 2. Simplified scheme of activators and effectors of both mTOR complexes, together with effects of mTOR inhibition using different mTOR inhibitors

mTOR can be shared by two different complexes, mTORC1 and mTORC2. Phosphorylation of mTOR at Ser2448 and Ser2481 are indicative of mTORC1 and mTORC2 activation, respectively. mTORC1 can be activated by nutrients (amino acids, glucose), growth factors (Insulin, Insulin-like Growth Factor-1), hormones (leptin), and stresses (starvation, hypoxia, and DNA damage). Through mTORC1, these signals accelerate the synthesis of key proteins, involved in growth, division, metabolism and angiogenesis. mTORC1-activated p70 S6K1 and Grb10 mediate IRS-1 degradation, thus inhibiting PI3K/Akt activation. Grb10 also leads to negative feedback inhibition of MAPK/ERK pathway. Finally, activated p70 S6K1 inhibits mTORC2 signaling by phosphorylating Rictor on Thr1135. Allosteric mTOR inhibitors exert an incomplete inhibition of mTORC1 and are inactive against mTORC2 under short-term conditions. Moreover, they disrupt the mTORC1-dependent negative feedback loop to IRS-1/PI3K, MAPK/ERK and mTORC2. As a consequence, treatment with mTOR allosteric inhibitors often results in increased mTORC2 activity. mTORC2 functions upstream of Akt providing the critical second phosphorylation of Akt at Ser473, which is necessary for Akt full activation. mTORC2 also regulates cytoskeletal dynamics by activating PKCα, and regulates growth via SGK1 phosphorylation. The upstream regulation of mTORC2 is not well defined although ribosome association appears to be a major, if not the sole, mechanism of mTORC2 activation. Catalytic mTOR inhibitors are able to suppress activity of both mTORC1 and mTORC2 complexes, avoiding oncogenic signaling pathway activation