mTOR Cross-Talk in Cancer and Potential for Combination Therapy

Abstract

The mammalian Target of Rapamycin (mTOR) pathway plays an essential role in sensing and integrating a variety of exogenous cues to regulate cellular growth and metabolism, in both physiological and pathological conditions. mTOR functions through two functionally and structurally distinct multi-component complexes, mTORC1 and mTORC2, which interact with each other and with several elements of other signaling pathways. In the past few years, many new insights into mTOR function and regulation have been gained and extensive genetic and pharmacological studies in mice have enhanced our understanding of how mTOR dysfunction contributes to several diseases, including cancer. Single-agent mTOR targeting, mostly using rapalogs, has so far met limited clinical success; however, due to the extensive cross-talk between mTOR and other pathways, combined approaches are the most promising avenues to improve clinical efficacy of available therapeutics and overcome drug resistance. This review provides a brief and up-to-date narrative on the regulation of mTOR function, the relative contributions of mTORC1 and mTORC2 complexes to cancer development and progression, and prospects for mTOR inhibition as a therapeutic strategy.

Keywords: cancer; cross-talk; mTORC1; mTORC2; targeted therapies.

Figure 1

mammalian Target of Rapamycin (mTOR) complexes. mTOR protein forms two unique complexes, called mTOR complex (mTORC)1 and mTORC2. mTORC1 is activated by growth factors, amino acids, and energy levels, whereas mTORC2 is primarily responsive to growth factors. mTORC1 is comprised of the core proteins mTOR, Regulatory-associated protein of mTOR (Raptor), and mLST8; mTORC1 also binds other proteins in a species- and condition-specific manner: Proline-Rich AKT Substrate 40 (PRAS40), DEP domain-containing mTOR interacting protein (DEPTOR), GRp58, Tel2-interacting protein 1 (Tti1)- Telomere maintenance 2 (Tel2) and Rac1. mTORC2 includes the core proteins mTOR, Rapamycin insensitive companion of mTOR (Rictor), and mammalian Lethal with Sec13 protein 8 (mLST8), as well as various associated proteins, Proline-Rich Protein (PRR)5, Heat shock protein (Hsp) 70, DEPTOR, GRp58, Tti1-Tel2, Rac1, mammalian Stress-activated protein kinase Interacting protein (mSIN) 1 and Protein observed with RICTOR (Protor). mTORC1 regulates numerous processes including cell growth and proliferation, biosynthesis of macromolecules (proteins, DNA, and lipid synthesis), and angiogenesis, by regulating p70 ribosomal protein S6 Kinase 1 (p70^S6K1) and Elongation Initiation Factor (EIF)-4E Binding Protein 1 (4E-BP1). mTORC2 controls cell structure, cytoskeletal reorganization, and survival by activating Serum and Glucocorticoid Kinase (SGK), Protein kinase B (AKT), and Protein-Kinase C (PKC).

Figure 2

Cross-talk of mTOR with other signaling pathways. The RAS/Mitogen Activated Protein Kinase (MAPK) and phosphoInositide3-Kinase (PI3K)/mTOR pathways respond to extracellular and intracellular stimuli and they extensively cross-talk to both positively and negatively regulate each other. Growth factors bind Receptor Tyrosine Kinases (RTK), which activate both MAPK and PI3K pathway, by regulating a cascade of phosphorylations. Activated MAPK signaling both positively and negatively regulates the activity of members of PI3K/mTOR pathway, by interfering with the assembly of Tuberous Sclerosis Complexes (TSC) 1-TSC2 complex. Activated PI3K phosphorylates PhosphatidylInositol Phosphate (PIP) 2 to generate membrane-bound PIP3, which in turn activates AKT. mTORC1 and mTORC2 activation regulates cell survival, proliferation, motility, angiogenesis, translation and metabolism. Black arrows represent positive signaling, whereas the red ones represent negative regulations.

Figure 3

mTOR and STAT signaling interaction in immune response. Cytokines bind trans-membrane receptors, which activate intracellular signaling, such as MAPK, STAT and PI3K/mTOR. These pathways cross-regulate each other to modulate the activity of immune cells.