Therapeutic targeting of the mTOR‐signalling pathway in cancer: benefits and limitations

Abstract

The mammalian target of rapamycin (mTOR) plays an important role in the regulation of protein translation, cell growth and metabolism. The mTOR protein forms two distinct multi-subunit complexes: mTORC1 and mTORC2. The mTORC1 complex is activated by diverse stimuli, such as growth factors, nutrients, energy and stress signals; and essential signalling pathways, such as PI3K and MAPK, in order to control cell growth, proliferation and survival. mTORC1 also activates S6K1 and 4EBP1, which are involved in mRNA translation. The mTORC2 complex is resistant to rapamycin inhibitory activity and is generally insensitive to nutrient-and energy-dependent signals. It activates PKC-α and Akt and regulates the actin cytoskeleton. Deregulation of the mTOR-signalling pathway (PI3K amplification/mutation, PTEN loss of function, Akt overexpression, and S6K1, 4EBP1 and eIF4E overexpression) is common in cancer, and alterations in components of the mTOR pathway have a major role in tumour progression. Therefore, mTOR is an appealing therapeutic target in many tumours. Here we summarize the upstream regulators and downstream effectors of the mTORC1 and mTORC2 pathways, the role of mTOR in cancer, and the potential therapeutic values and issues related to the novel agents targeting the mTOR-signalling pathway. AbbreviationsDeptor, DEP-domain-containing mTOR-interacting protein; EGFR, epidermal growth factor receptor; eIF4E, translation initiation factor 4E; FKBP12, FK506-binding protein; GSK3, glycogen synthase kinase 3; HIF-1α, hypoxia inducible factor-1α; Hsp70, heat shock protein 70-α; IGFR, insulin-like growth factor receptor; mLST8, mammalian lethal with Sec13 protein8 (also known as GβL); mSIN1, mammalian stress-activated protein kinase-interacting protein 1; mTOR, mammalian target of rapamycin; mTORC1 and mTORC2, mTOR complex 1 and 2; PDK1, 3-phosphoinositidedependent protein kinase-1; PI3K, phosphoinositide 3-kinase; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PRAS40, proline-rich Akt substrate 40 kDa; PTEN, phosphatase and tensin homologue; Raptor, regulatory-associated protein of mTOR; Rictor, Raptor-independent companion of mTOR; RTK, receptor tyrosine kinase; S6K1, S6 kinase 1; TPdIs, mTOR/PI3K dual inhibitors; TSC1 and TSC2, tuberous sclerosis 1 and 2 complex BJP British Journal of Pharmacology

Targeting translation: eIF4E as an emerging anticancer drug target

“…Naturally, targeting mTOR signalling pathway is a therapeutically attractive option for the purpose of sequestering eIF4E because 4EBPs are direct substrates of mTOR kinase (Ref. 130).…”

Glucose deprivation attenuates sortilin levels in skeletal muscle cells

“…In this age-associated sarcopenia, it has been demonstrated that mTORC1 signaling is negatively controlled in those atrophied skeletal muscle cells [36,37]. As described, the reduction of glucose or amino acids can inactivate mTORC1 followed by decreased protein translation in skeletal muscle [30,31]. Because the small interference RNA-mediated suppression of endogenous sortilin inhibited C2C12 differentiation [7], it is indeed possible to speculate that the mTORC1-dependent sortilin regulation may contribute to the loss of skeletal muscle mass.…”

“…Two major downstream targets for mTORC1 are also well defined, p70 S6 kinase (S6K1) and 4E-BP1. Phosphorylation of S6K1 at Thr389 by mTORC1 is a trigger for its activation [29], and the activated S6K1 phosphorylate S6 ribosomal protein, subsequently enhances the translation of mRNAs that have 5′ terminal oligopolypyrimidine [30]. On the other hand, 4E-BP1 normally binds to eukaryotic translation initiation factor 4E (eIF4E) and inhibits eIF4E-dependent protein translation.…”

Two novel STK11 missense mutations induce phosphorylation of S6K and promote cell proliferation in Peutz‑Jeghers syndrome

“…Furthermore, activation of mTORC1 inhibits autophagy via phosphorylation of autophagy-related protein 13 and ULK1/2 (44). Rapamycin, a specific mTOR inhibitor, has been developed as an effective drug for the treatment of PJS and its associated tumors (22,45).…”