Does Temsirolimus inhibit mTORC2 with prolonged or high dosing?

Has anyone looked into this issue?

@KarlT brings up this issue in this posting:


Not many mentions of this drug. Would be hard to use, but some papers indicate it is a selective mtorc1 inhibitor without mtorc2 inhibition.

Has anyone looked in depth into the issue as to whether Temsirolimus might be a drug that avoids the mTORC2 inhibition that we see eventually with rapamycin and everolimus?

Here is what I’ve found so far… while its classified (like all rapalogs) as strictly an mTORC1 inhibitor, we all know that there is some sort of feedback mechanism with prolonged, high-dose rapamycin and everolimus use , that eventually results in mTORC2 suppression.

The question is, does Termsirolimus have that same problem of eventual mTORC2 inhibition with prolonged or high dosing?

Rapamycin (also named sirolimus, Wyeth) and other rapalogues including temsirolimus (CCI-779, Wyeth), everolimus (RAD001, Novartis Pharmaceutical), and deforolimus (AP23573, Ariad Pharmaceutical) are macrocyclic lactones acting as anticancer agents that target mTOR in several human cancers in vitro and in vivo. The main differences between rapalogues lie in changes in chemical properties in terms of drug solubility and metabolism. As a result, temsirolimus and deforolimus are water soluble and may be administered intravenously, whereas rapamycin and everolimus display low solubility, and therefore are available only for oral formulations. Rapalogues bind very similarly to the intracellular immunophilin-, FK506, binding protein-12 (FKBP12) and selectively inhibit mTORC1, but have no direct effects on mTORC2. Potency to inhibit mTORC1 seems to be identical across rapalogues. The inhibitory effects of rapalogues on mTORC1 do not seem to affect the kinase activity of mTOR. Although limited experiments have been carried out to benchmark and address cross-resistance between rapalogues, similarities in terms of chemical structures, mechanisms of action, affinity for the target, and overall spectrum of activity in laboratory experiments strongly suggest that currently developed rapalogues are similar in many ways, the main differences belonging to pharmacokinetic properties rather than to antitumor potency.


In our study, temsirolimus produced a transient decrease in the phosphorylation of AKT on Ser473 and Thr308, which are considered mTORC2 phosphorylation sites. This suggests that temsirolimus has some direct or indirect effect on this particular mTORC2-regulated phosphorylation. The effect may be brief because mTORC1 inhibition removes negative feedback loops targeting AKT; and increased AKT activity quickly overcomes any minor mTORC2 inhibition provided by temsirolimus.


Interesting… it says something similar in the other paper:

Interestingly, sustained exposure to rapamycin was shown to secondarily inhibit mTORC2, as most of the mTOR bounded to rapamycin/FKBP12 is unavailable to complex with rictor. Those data may suggest that resistance to rapamycin may be associated with the activation of AKT, a mechanism that may be at least in part prevented using sustained exposure to rapamycin to block both mTORC1 and mTORC2. Thereby, antitumour activity may depend not only on the type of rapalogues and doses used in the clinic, but also on the duration of drug administration/exposure. Sustained exposure may increase the potency of rapalogues by inhibiting mTORC1 as well as mTORC2. Considering the half-life of rapalogues (see below), maximal mTOR inhibition may be achieved using continuous daily oral dosing of everolimus, whereas temsirolimus that is slowly biotransformed into sirolimus can be given intravenously only once a week.

But I think the key point here is that Temsirolimus is a “prodrug” for sirolimus; which means it gets converted in the body to sirolimus. So I suspect you are going to have exactly the same mTORC2 response eventually, as with just taking the drug sirolimus directly…

Pharmacokinetic analysis showed that temsirolimus was converted into sirolimus, and exposure to sirolimus was prevalent in plasma several days after a single infusion of temsirolimus (Raymond et al, 2004; Hidalgo et al, 2006).

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This may explain why high dose Rapa doesn’t negatively impact mtorc2, at least in the short term.

This looks like a good paper on the topic:

While rapamycin acutely and directly inhibits mTORC1, only chronic administration of rapamycin can inhibit mTORC2 in some, but not all, cell lines or tissues. The mechanism leading to cell specificity of mTORC2 inhibition by rapamycin is not understood and is especially important because many of the negative metabolic side effects of rapamycin, reported in mouse studies and human clinical trials, have been attributed recently to mTORC2 inhibition. Here, we identify the expression level of different FK506-binding proteins (FKBPs), primarily FKBP12 and FKBP51, as the key determinants for rapamycin-mediated inhibition of mTORC2.


While mTORC1 inhibition by rapamycin is universal, only 15 of 39 cell lines tested were responsive to mTORC2 inhibition by rapamycin (Sarbassov et al ., 2006).

It is well described that rapamycin leads to the inhibition of mTORC1 in vivo , but the effects of rapamycin on mTORC2 in individual tissues have not been clearly established and is critical to understand the effects of rapamycin in vivo . To address this issue, we IP injected 10-week-old mice with 8 mg kg−1 rapamycin every other day for 3 weeks.

As expected, inhibition of the phosphorylation of the mTORC1 substrate, S6 (S240/244), was seen in every tissue tested, but mTORC2 inhibition, measured by the phosphorylation of Akt (S473), was only seen to differing degrees in a subset of tissues including heart, soleus muscle, gastrocnemius muscle, pancreas, liver, lung, visceral fat, and spleen (Figs​(Figs6A6A,​,BB,​,CC and S3). mTORC2 inhibition was heightened by these harvesting conditions, because under harvesting conditions where mice were starved for only 6 h without insulin stimulation, only heart, soleus, gastrocnemius, and pancreas are responsive to mTORC2 inhibition (Fig. S4). Tissues that are completely unresponsive to mTORC2 inhibition under either experimental condition include thymus, kidney, and stomach (Figs​(Figs6C,6C, S3…

In some tissues/diseases, such as cancer, it will likely be beneficial to inhibit both mTORC1 and mTORC2 where others, such as the aging process in general, might benefit from mTORC1-selective inhibition to avoid the negative metabolic side effects associated with prolonged treatment of the drug (Stallone et al ., 2009; Houde et al ., 2010). Current literature supports that the inhibition of mTORC1 contributes to the longevity effects of rapamycin and the inhibition of mTORC2, specifically in the liver, causes the negative effects of rapamycin on glucose homeostasis.

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I haven’t come across extensive research on Temsirolimus specifically regarding mTORC2 inhibition compared to other rapalogs like Rapamycin and Everolimus. It appears that while Temsirolimus is primarily classified as an mTORC1 inhibitor, questions remain about its potential for mTORC2 suppression with prolonged or high dosing. More focused studies may be needed to clarify this aspect of Temsirolimus’s mechanism of action.