mTOR inhibitors

Author: Alessandro Bernardi Laura Pittana
Date: 23/02/2011



Mammalian target of rapamycin is a kinase that functions as a master switch between catabolic and anabolic metabolism and as such is a target for the design of anticancer agents. The most established mTOR inhibitors —rapamycin and its derivatives — showed long-lasting objective tumour responses in clinical trials, that improved the survival of patients with advanced renal cell carcinoma. This heralded the beginning of extensive clinical programmes to further evaluate mTOR inhibitors in several tumour types.

Mammalian Target of Rapamycin (mTOR) Pathway

Three primary signaling pathways associated with RTKs are currently identified in cancer cells. One of them is the phosphoinositide 3-kinase (PI3K)/Akt/mTOR protein cascade; the other two are the protein kinase C family and the Ras/mitogen-activated protein kinase cascades. Activation of RTK leads to stepwise activation of PI3K, then Akt, and then mTOR, directly promoting tumor growth. The mutation and overexpression of RTK, as well as growth receptors, are common in RCC.

mTOR regulates essential signal-transduction pathways, tying growth stimuli to cell-cycle progression. It also integrates signals involving nutrient availability, energy status, and stress. There are two multiprotein complexes (mTORCs): mTORC-1 and mTORC-2. mTORC-1 is rapamycin-sensitive; mTORC-2 is rapamycin-insensitive.

The mTOR pathway is important with regard to glucose and lipid metabolism. Interruption of the pathway by mTOR inhibitors increases the frequency of hyperglycemia, hypercholesterolemia, and hyperlipidemia.

mTOR Inhibitors


Rapamycin , also known as sirolimus, originally was developed as an antifungal drug, but it was initially used as an immunosuppressive agent in transplant patients because it inhibits T-cell proliferation after activation. Rapamycin was not studied for its anticancer activity until the late 1990s, when it was identified as the first mTOR inhibitor.
To inhibit mTOR, rapamycin must bind to an abundant intracellular binding protein, FKBP-12; the drug:FKPB-12 complex binds at the rapamycin binding domain. The result of mTOR inhibition is cell-growth arrest, decreased protein synthesis, and reduced growth signaling. Rapamycin decreases the activity of mTORC-2 with sustained exposure.
Later rapamycin derivatives (rapalogues), include temsirolimus and everolimus, were developed. The primary difference between the rapalogues is their pharmacokinetic and pharmacologic properties. Temsirolimus was created by adding an ester to a rapamycin carbon, and adding an ether created everolimus; the result was increased solubility and bioavailability. Notably, the rapalogues do not induce immunosuppression, as is seen with rapamycin.


Temsirolimus, also known as CCI-779, is an administered mTOR kinase inhibitor. The agent inhibits cell division, halts growth signaling, and reduces hypoxia inducible factor (HIF-1 and HIF-2 alpha) and VEGF expression.

Temsirolimus binds to FKBP-12, forms a complex, and inhibits mTOR signaling. It is hydrolyzed to the active metabolite sirolimus, which also likely inhibits mTOR. Temsirolimus has a terminal half-life of 12 to 15 hours; that of sirolimus is 40 to 50 hours. Temsirolimus is metabolized hepatically via CYP450 3A4 Drug interactions can occur with strong inducers and inhibitors, so these medications should be avoided. Grapefruit juice should be avoided because it may increase sirolimus levels.
The dosing is 25 mg once weekly as a 30- to 60-minute infusion. To prevent a hypersensitivity reaction, the patient should receive diphenhydramine 25 mg or 50 mg, or a similar antihistamine, about 30 minutes before the start of each dose. The dose should be held in the event of low neutrophil or platelet counts or severe adverse reactions.

Dose reductions and delays were least common in the temsirolimus single-agent arm. The FDA approved temsirolimus for metastatic RCC in May 2007, so temsirolimus is now favored as first-line treatment for patients with poor-prognosis metastatic RCC.


Everolimus, also known as RAD001, is an orally administered mTOR kinase inhibitor. It forms a complex with the intracellular protein FKBP-12 and inhibits the mTOR kinase. Everolimus reduces cell proliferation, cell growth, angiogenesis, and glucose uptake, and it inhibits HIF-1 expression and reduces VEGF expression.

Everolimus is administered once daily as a 10-mg tablet, at the same time every day, with or without food. It is metabolized hepatically via CYP450 3A4. Drug interactions with CYP450 3A4 inducers and inhibitors should be avoided. The dose of everolimus may also be reduced to 5 mg in the presence of moderate hepatic impairment or severe adverse events. The mean half-life is about 30 hours. There are six main metabolites of everolimus; they are 100 times less potent than the parent compound. Grapefruit juice should be avoided.


  • Scheda Tecnica del Seguente Nuovo Farmaco Autorizzato dalla Commissione
    Europea all'Immissione in Commercio in Data 05 Agosto 2009
    - Farmaco : Afinitor (Compresse)
    - Principio Attivo : Everolimus
    E' un Inibitore Selettivo del mTOR (Mammalian Target of Rapamycin, Target della
    Rapamicina nei Mammiferi), mTOR e' una Serin-Treonin Chinasi Chiave la cui
    Attivita' e' Nota per Essere Sovraregolata in un Numero di Tumori nell'Uomo
    - ATC : L01XE10
    - Categoria Farmacoterapeutica : Inibitori della Protein-Chinasi
    - Indicazione Terapeutica : Trattamento di Pazienti con Carcinoma Renale Avanzato
    che Hanno Presentato Progressione Durante o Dopo Trattamento con Terapia
    Mirata Anti-VEGF

mTORC2 inhibitors

Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy. 2010

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.

Adverse Events

The primary adverse-events profile of the mTOR inhibitors includes hyperglycemia and hyperlipidemia .
This reflects the blockade of mTOR, the primary signaling conduit for insulin and insulin growth factor. Other common adverse events for temsirolimus and everolimus include fatigue, stomatitis, diarrhea, hypophosphatemia, low red blood cells and platelets, and peripheral edema. These adverse events are commonly reversible upon treatment discontinuation. Less common symptoms are renal insufficiency, interstitial pneumonitis, and low white blood cells.

Guertin DA

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