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Review
. 2010 Jul 1;29(26):3733-44.
doi: 10.1038/onc.2010.139. Epub 2010 Apr 26.

Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy

C A Sparks  1 , D A Guertin
Affiliations
Review

Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy

C A Sparks et al. Oncogene. .

Abstract

Small molecule inhibitors that selectively target cancer cells and not normal cells would be valuable anti-cancer therapeutics. The mammalian target of rapamycin complex 2 (mTORC2) is emerging as a promising candidate target for such an inhibitor. Recent studies in cancer biology indicate that mTORC2 activity is essential for the transformation and vitality of a number of cancer cell types, but in many normal cells, mTORC2 activity is less essential. These studies are intensifying interest in developing inhibitors that specifically target mTORC2. However, there are many open questions regarding the function and regulation of mTORC2 and its function in both normal and cancer cells. Here, we summarize exciting new research into the biology of mTORC2 signaling and highlight the current state and future prospects for mTOR-targeted therapy.

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Conflict of interest statement

Conflict of interest

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The mTORC1 and mTORC2 signaling branches. mTOR is the catalytic subunit of two complexes called mTORC1 and mTORC2. mTORC1 is sensitive to growth factors, hypoxia, low energy, and amino acids. The TSC1–TSC2 complex coordinates the growth factor, oxygen, and energy inputs to mTORC1 by negatively regulating the Rheb GTPase, which directly activates mTORC1. The Rag-GTP-binding proteins regulate the amino-acid input to mTORC1 by an independent mechanism. mTORC1 controls protein synthesis through 4E-BP1 and S6K1 and regulates mitochondrial biogenesis and lipid synthesis while inhibiting autophagy by less defined mechanisms. Less is known about mTORC2 signaling. Receptor tyrosine kinase (RTK) signaling activates mTORC2 through the PI3K/PTEN pathway, but the mechanism has not been elucidated. When active, mTORC2 phosphorylates the AGC kinases AKT, SGK, and PKC, which have multiple functions in controlling cell survival, metabolic regulation, and cytoskeletal organization. AGC kinases are co-regulated by mTORC2 and PDK1, and the coordinate phosphorylation by both is required for maximal kinase activity (PDK1-dependent S6K phosphorylation is not shown). Negative feedback loops and crosstalk between both branches of the mTOR network have important implications in mTOR-targeted therapy. S6K1 mediates well-known negative feedback loops (red) that attenuate PI3K-AKT signaling in response to mTORC1 activation, the best known being direct phosphorylation and inactivation of insulin receptor substrate-1 (IRS-1). An emerging function for direct negative and positive regulation of mTORC2 by S6K1 and TSC1/2, respectively, may contribute to negative feedback regulation to ensure AKT signaling is low when mTORC1 is active.
Figure 2
Figure 2
The mTORC2 components. (a) mTORC2 consist of the mTOR catalytic subunit and at least five accessory proteins. Rictor, mSIN1, and Protor are unique subunits of mTORC2. In contrast, mLST8 and Deptor are shared subunits of mTORC1 and mTORC2. Rictor, mSIN1, and mLST8 (in addition to mTOR) are the core essential components of the complex and are required for maintaining structural integrity. In contrast, mTORC2 activity does not require Deptor and Protor, which may function as regulatory proteins. Deptor seems to negatively regulate mTORC2, whereas the function of Protor is unknown. (b) Domain structures of the mTORC2 subunits. mTOR is a large protein (~250 kDa). It contains a C-terminal kinase domain and N-terminal HEAT repeats. Immediately upstream of the kinase domain is the FKBP12-rapamcyin-binding (FRB) domain. mTOR contains a number of phosphorylation sites in its C-terminus, and phosphorylation at one of them (S2481) associates only with mTOR proteins assembled into mTORC2. mLST8 is almost entirely composed of WD repeats. Rictor has no obvious functional domains, but contains a stretch in the C-terminus that is conserved only in vertebrates and is heavily phosphorylated. The T1135 phosphorylation site is targeted by S6K1. mSIN1 exists in at least three isoforms that independently associate into mTORC2 complexes, perhaps defining three unique versions of mTORC2. The full-length mSIN1.1 isoform contains a ras-binding domain (RBD) and pleckstrin homology domain (PH). The mSIN1.2 isoform lacks a portion of the RBD, whereas the mSIN1.5 isoform lacks a different portion of the RBD and the entire PH domain. Protor exists in two isoforms, which share homology in their amino-terminal haves. Deptor contains amino-terminal DEP (disheveled, eg-l10, pleckstrin) domains and a C-terminal PDZ (postsynaptic density 95, discs large, zonula occludens-1) domain.
Figure 3
Figure 3
Possible mechanisms by which a small molecule could inhibit mTORC2. (a) An mTORC2-specific inhibitor could function by blocking the assembly of mTORC2 components or by destabilizing protein–protein interactions within the complex. Biochemical studies indicate that dissociating Rictor, mSIN1, or mLST8 will destabilize the complex. (b) One of the mTORC2 subunits might function as a scaffold for recruiting substrates and a small molecule could block the substrate-binding interface. (c) Perhaps mTORC2 is targeted to the plasma membrane where it phosphorylates AKT. A small molecule that could bind its membrane-targeting domain might inhibit mTORC2-dependent AKT phosphorylation. However, membrane-independent functions of mTORC2 would likely be unaffected by such a compound. (d) Small molecule inhibitors could also target an mTORC2 upstream-activating kinase.
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