Mighty mTOR. Should we fight it to cure cancer?

MIGHTY MTOR: SHOULD WE FIGHT IT TO CURE CANCER?

WHY MTOR

When thinking about signalling pathways involved in cancer, p53 and src usually come to mind first. However, with the genomics and metabolomics progress new pro- and anti-oncogenic mechanisms are described every day. And one signalling pathway stand out as the most promising candidate for research.

It seems like mammalian target of rapamycin (mTOR) ‘regulates everything’. It is involved in a whole range crucial processes on cell and organism levels: cell cycle, glycolysis, lipogenesis, gene transcription and protein translation, autophagy and immune cells specialization [1].

mTOR as serine/threonine protein kinase belongs to the phosphoinositide-3-kinase- related family. Being a signalling kinase its mechanism of regulation is altering the protein’s substrate recognition via phosphorylation[2].

MTOR SIGNALLING PATHWAY

mTOR is actually two different molecular complexes: mTORC1 and mTORC2. Both structures are well characterized.

mTOR complex 1 contains the mammalian lethal with Sec13 protein 8 (mLST8), the proline-rich Akt substrate of 40 kDa (PRAS40), the DEP domain containing mTOR-interacting protein (deptor) and mTOR (raptor) itself[3].

mTORC2 consists of mTOR and mLST8 as well, but also of proline-rich protein 5 (PRR5), mammalian stress-activated protein kinase-interacting protein 1 (mSin1), rapamycin-insensitive companion of mTOR (rictor) and protein observed with its loss or overregulation lead to major consequences[3].

More than that, there is a wide range of mTOR upstream regulators and downstream effectors. There are many representations for this network, but due to its complexity it is impossible to show everything in one scheme. I have chosen the pathway displaying not only sequential intracellular molecules activation but also membrane receptors which binding with specific agonist can trigger this process [figure 1].

The core process of this pathway could be described like this: being activated by some trigger phosphatidylinositol-3-kinase (PI3K) activates the serine/threonine protein kinase Akt (PKB), which inhibits TSC2, normally inhibiting GTPase Rheb. Thus, dual inhibition activates mTORC1, which in turn controls several pathways involved in translational control (4E-BPS, S6K1 and 2), lipid synthesis, mitochondrial function etc[4].

Thus, this pathway integrates diverse inputs, including neurotransmitters, immune signals and metabolic changes, to make crucial decisions, like whether to grow, to proliferate, to consume more energy or synthesize a protein.

MTOR IN CANCER

Being involved in major biochemical and physiological mechanisms, mTOR pathway inevitably contributes in cancer. It promotes cell proliferation and stimulates angiogenesis. It is also shown to be one one of the main mediators in Warburg effect[5].

Dysregulation of two mTOR complexes, and also PI(3)K, as well as hyperactivation of mTORC1 and its upstream regulator Rheb (Ras homolog enriched in brain) have been reported has been shown in renal cell carcinoma[6].

illustration not visible in this excerpt

Figure 1. MTOR SIGNALLING PATWAY[21].

NMDA receptor, N-methyl-D-aspartate receptor is a glutamate receptor; TrkB, tyrosine receptor kinase b; IRS-1, insulin receptor substrate 1; mTOR, mammalian target of rapamycin; PDK1, phosphatidylinositol-dependent kinase 1; Akt, RAC-alpha serine/threonine-protein kinase; PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-trisphosphate; RHEB, RAS homolog enriched in brain; eEF2K, eukaryotic elongation factor-2 kinase; TSC, tuberous sclerosis complex; S6K, ribosomal s6 kinase. P denotes phosphorylation sites[21].

Mutations in PI3K alpha catalytic subunit kinase domain (PIK3CA) and phosphatase and tensin homolog (PTEN) has been shown in patients with colorectal cancer[7], which is a most widespread cancer type in Hong Kong.

Thus, the role of mTOR in cancer progression is controversial. It can be considered as both a tumour-suppressor and proto-oncogene[8].

Though only few point mutations have been found in mTOR itself, its ‘rheostat’ position in a complex signalling network made it a promising therapeutic target in treating cancer.

MTOR INHIBITORS

To treat cancer, it makes sense to decrease tumour neovasculargenesis, cancer cell proliferation and energy consummation. That is where researches turn to mTOR pathway inhibition as a potential treatment.

Since the discovery of mTOR, rapamycin still remains its common inhibitor in research. However, the usage of rapamycin derivatives — rapalogs, such as sirolimus, everolimus, — is more widespread in clinical practice[9].

There also ATP-site competitive agents like PP242 and Torin 1, which are potentially more selective[10].

All these, and similar agents, are already being used as anticancer drugs, but the outcome is not always desirable. There are several reasons which could explain occasional mTOR inhibition inefficacy[11]:

1) Insufficient inhibition,
2) Drug resistance[12],
3) Immune suppression[13],
4) Feedback regulatory loops (via mTORC1 and mTORC2),
5) Overall system complexity.

To overcome these difficulties several solutions have been proposed. Sometimes simultaneous inhibition of two pathways, e.g. mTOR and RAF signalling, can be efficient even in cases when tumour is drug resistant for either of singular inhibitor[14]. More then that, combinations of these drugs with conventional therapies, like radio-, chemo- and genetic therapy, could also be more efficient.

And the whole new pool of potential inhibitors is yet to be discovered. Non- coding RNA can be a potential tumour suppressor agent through the PI3K/Akt/mTOR signalling pathway. For example, recent study shows, that microRNA-7 reverses the metastasis hepatocellular carcinoma[15].

It could also be that a dosage of already known inhibitors is insufficient for making a difference.

On the other hand, a complete shutdown of the whole pathway would be probably lethal. After all, even partial inhibition of one or the complexes increases a risk of such adverse effects as hyperlipidaemia, stomatitis, nausea, diarrhoea and infection[3].

Another problem is a diversity of phenotypes and genotypes both in preclinical and clinical models, so there is probably no universal solution possible. Yet, with the individual pharmacology approach in perspective usage, we could find predictive bio- markers of response in order to select a group of cancer patients, which will better response for this treatment.

For these purposes, such techniques as ribosome profiling and tumour genome sequencing are already used.

CONNECTION TO OTHER DISEASES

Besides cancer, mTOR deregulation has been linked to other clinical pathologies as well. Just to mention the identified ones would make a substantial list: diabetes, obesity, cardiovascular diseases, metabolic disorders, neurological disorders and aging [1]. E.g., researchers have already tried to manipulate components of mTOR signalling pathway to influence an animal lifespan[16].

As a neurobiologist, I was particularly interested in mTOR contribution to autism, epilepsy, schizophrenia, depression and major neurodegenerative diseases: Alzheimer’s disease, Parkinson’s disease, Huntington’s disease[17]-[21].

Particularly interesting is mTOR pathway activation by major excitatory neurotransmitter — glutamate. It involves Ca2+ influx, and the subsequent activation of p60src, phosphatidylinositol 3-kinase, protein kinase B, mTOR and p70S6K[22]. Since glutamate pathway is a well established player in epilepsy, mTOR could be the missing link in brain cancer and seizures comorbidity, as well[23].

It is interesting that one if the most common neurological problems — depression — is proposed to be treated with ketamine, which stimulates mTOR[24]. Could it be dangerous way to treat depression? Yes, as we consider the increasing oncogenic risk[25].

CONCLUSION

As every road leads to Rome, every process in cell is somehow connected with mTOR. It is one of the key players in myriad phenomena: metabolism, cell growth and survival, synaptic plasticity and memory, immunity and, essentially, aging.

As a consequence, its dysregulation leads to severe pathology, from cancer to psychiatric syndromes. And it has been shown that down-regulation of this pathway, e.g. mTOR inhibition can be beneficial for dealing with symptoms of these diseases[11]. At the same time, for other cases, like depression treatment and immune stimulation, up-regulation is needed. So, tinkering with such a complex pathway in both directions we are facing the risk of severe side-effects.

In other words, we must definitely study mTOR signalling network and its role in cancer and other diseases. It means to proceed with looking for mutations, individual genome variances and dysregulations of this components. However, due to complexity and too many functions, pharmacologists should strive for fine-tuning this pathway via feedback loops, not switching mTOR off completely.

Ekaterina, KOPEIKINA

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