mTOR Inhibitors

mTOR, the mammalian target of rapamycin, is a protein kinase that regulates a wide range of cellular functions. It forms two distinct multiprotein complexes, designated mTOR complexes 1 and 2 (mTORC1 and mTORC2). Each complex plays key roles in cellular regulation. mTORC1 controls multiple anabolic pathways, including protein synthesis, ribosome production, lipogenesis, and nucleotide synthesis, all of which are important for cell and tissue growth. mTORC1 also suppresses a key catabolic process, autophagy , by inhibiting its activation and by suppressing the production of lysosomes, the organelles responsible for autophagy. mTORC1 also phosphorylates the proteins involved in these pathways, thereby altering their activity or subcellular localization (1).

A fundamental characteristic of cancer cells is their ability to sustain chronic proliferation in the absence of growth-promoting signals. This is achieved in part by genetic events that cause aberrant activation of mTORC1 signaling (2). Accordingly, mTORC1 signaling is hyperactive in the majority of cancers. Inhibiting mTORC1 signaling has therefore attracted great attention as an anti-cancer therapy.

There are three classes of mTOR inhibitors currently available for cancer treatment.

Rapamycin and rapalogs

The natural antibiotic and antifungal agent rapamycin was the first mTOR inhibitor identified. However, rapamycin does not directly inhibit the catalytic (kinase) activity of mTOR; instead, it forms a complex with the FKBP12protein, binding specifically to mTORC1 (but not mTORC2) near the kinase active site. The rapamycin /FKB12 complex prevents the contact between mTORC1 and its substrates and selectively interferes with mTORC1 function (3). It however inhibits only some of mTORC1 functions.

The anticancer activity of rapamycin is well documented (4); however, the results of clinical trials have been disappointing. As the solubility and bioavailability of rapamycin are low, more soluble rapamycin derivatives analogs (rapalogs) were developed (3)

Temsirolimus (Torisel®) is a rapamycin ester derivative, approved by the FDA for the treatment of advanced-stage (metastatic) renal cell carcinoma. It is available in both intravenous and oral formulation.

Everolimus (Afinitor®) is FDA-approved for the treatment of advanced renal carcinoma, subependymal giant cell astrocytoma associated with tuberous sclerosis, advanced neuroendocrine tumor of pancreatic origin, neuroendocrine tumors of gastrointestinal or lung origin (5) and certain breast cancers. It is delivered orally.

Ridaforolimus (aka AP23573 and MK-8669) is currently being tested for the treatment of metastatic soft-tissue and bone sarcoma (6). It may be given orally or intravenously.

Everolimus and temsirolimus are also currently tested in additional cancer types, alone or in combination with other drugs (6).

The effects of rapalogs as cancer monotherapy have been limited, perhaps because they only exhibit poor proapoptotic activity, being mainly cytostatic. Rapalogs also do not fully inhibit mTORC1 activity. Combination of rapalogs with other therapies may possibly overcome these limitations (7).

The next section describes mTOR inhibitors that effectively inhibit both mTORC1 and mTORC2.

Dual PI3K/mTOR inhibitors

The PI3K/AKT/mTOR pathway is an intracellular signaling pathway regulating the cell cycle. It is one of the most commonly up-regulated signal transduction cascades in human cancers.

PI3K and mTOR both belong to the PIKK superfamily of kinases and have high sequence homology in their catalytic domains. As a result, it has been discovered that several PI3K inhibitors developed in drug discovery projects can effectively suppress the activation of both mTOR complexes. These drugs are classified as dual PI3K/mTOR inhibitors. The high potential of these drugs as anti-cancer agents stems from the simultaneous inhibition of PI3K and mTOR, two crucial signaling hubs promoting cancer cell growth.

This class of inhibitors is currently being tested for the treatment of both solid and hematological malignancies (3). Compounds include the imidazoquinoline derivative NVP-BEZ235  developed by Novartis, and GSK2126458 from GlaxoSmithKline  (1).These compounds display a more potent apoptotic activity and more complete inhibition of mTORC1 outputs than rapamycin/rapalogs (8, 9). They are however likely to display higher toxicity.

ATP-competitive mTORC1/mTORC2 inhibitors

Given the inability of rapamycin to affect all functions of mTORC1, compounds that inhibit the catalytic activity of mTOR itself were developed. These compounds can potentially inhibit all phosphorylation events catalyzed by mTORC1 and also affect mTORC2 (85). In preclinical studies, ATP-competitive mTORC1/mTORC2 inhibitors displayed more powerful anti-proliferative and pro-apoptotic effects, and more complete inhibition of mTORC1 outputs than rapalogs (3). Several of these drugs, e.g. sapanisertib, have been investigated in clinical trials for a wide variety of malignancies (3).

In conclusion, mTOR inhibition offer many opportunities for cancer treatment. However, development of safe and effective treatments is challenging because of the importance of mTOR signaling for normal cell functions. Current studies point at new directions, such as blocking relevant events downstream of mTORC1, and could offer new clinical opportunities.


  1. Xie J, Wang X, Proud CG. mTOR inhibitors in cancer therapy. F1000Research. 2016;5:F1000 Faculty Rev-2078.
  2. Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell. 2007;12(1):9-22.
  3. Chiarini F, Evangelisti C, McCubrey JA, Martelli AM. Current treatment strategies for inhibiting mTOR in cancer. Trends in Pharmacological Sciences. 2015;36(2):124-135.
  4. Guba M, von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nature Medicine. 2002;8(2):128-135.
  7. Cargnello M, Tcherkezian J, Roux PP. The expanding role of mTOR in cancer cell growth and proliferation. Mutagenesis. 2015;30(2):169-176.
  8. Chapuis N, Tamburini J, Green AS, et al. Dual Inhibition of PI3K and mTORC1/2 Signaling by NVP-BEZ235 as a New Therapeutic Strategy for Acute Myeloid Leukemia. Clinical Cancer Research. 2010;16(22):5424-5435.
  9. Chiarini F, Grimaldi C, Ricci F, et al. Activity of the Novel Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor NVP-BEZ235 against T-Cell Acute Lymphoblastic Leukemia. Cancer Research.2010;70(20):8097-8107.


Brand/Trade Names: Afinitor, Zortress

Formula: C53H83NO14

Mechanism: inhibits mTor


Administration: Oral

Notes: Sequencing and Role of Everolimus in HR-Positive Breast Cancer


Brand/Trade Names: Torisel

Formula: C56H87NO16

Mechanism: inhibits mTor


Administration: Intravenous

Notes: From NCI