Recent advances and limitations of mTOR inhibitors in the treatment of cancer

new paper:

The PI3K-Akt-mechanistic (formerly mammalian) target of the rapamycin (mTOR) signaling pathway is important in a variety of biological activities, including cellular proliferation, survival, metabolism, autophagy, and immunity. Abnormal PI3K-Akt-mTOR signalling activation can promote transformation by creating a cellular environment conducive to it. Deregulation of such a system in terms of genetic mutations and amplification has been related to several human cancers. Consequently, mTOR has been recognized as a key target for the treatment of cancer, especially for treating cancers with elevated mTOR signaling due to genetic or metabolic disorders. In vitro and in vivo, rapamycin which is an immunosuppressant agent actively suppresses the activity of mTOR and reduces cancer cell growth. As a result, various sirolimus-derived compounds have now been established as therapies for cancer, and now these medications are being investigated in clinical studies. In this updated review, we discuss the usage of sirolimus-derived compounds and other drugs in several preclinical or clinical studies as well as explain some of the challenges involved in targeting mTOR for treating various human cancers.

Recent phase II clinical studies with rapamycin for the treatment of multiple sclerosis have revealed promising outcomes [12]. To limit the potential undesired side effects of current mTOR inhibitors, it is important to identify more potent novel targets. ATP competitive inhibitors of mTOR, for example, OSI-027 and its analogues are promising anticancer drugs [74]. Furthermore, recently revealed crystal structures of the mTOR complex would provide new insights for the advancement of more powerful and efficient mTOR inhibitors in future. The clear-cut efficacy of rapamycin and rapalogues in multiple therapeutic settings has propelled interest to discover new types of inhibitors that may be more potent and eventually with fewer side effects than rapamycin and rapalogues that include ATP competitive mTOR inhibitors. The current review summarizes the use of sirolimus and its derivatives and addresses potential limitations in targeting mTOR signaling for the treatment of cancer.

Open access paper:


Another cautionary note about rapamycin and cancer. As one who has localized prostate cancer and just took his weekly dose of rapa, vexing. Essentially, the study was about how exercise inhibits mouse melanoma cancer from metastasis by competing for available nutrients that cancer cells need. Add rapamycin to the equation which puts mTOR-affected normal cells “at rest” in a sense, (“pseudo-senescence”) and cancer metastases increased. Also makes me wonder about the extensive supplement stack that I have taken for years in the context of supporting vs. defeating cancer.

Wrestling nutrients from cancer

Switching to in vitro, the researchers co-cultured cells taken from active and inactive mice with melanoma cells. In the presence of exercise-primed cells, melanoma cells seemed to fare far worse, with either decreased proliferation (when co-cultured with lung cells) or increased apoptosis (when co-cultured with liver and lymph node cells).

Because previous results suggested that increased metabolic activity causes more stiff competition and ultimately affects cancer progression, the researchers ran another interesting experiment: they treated cells taken from active mice with rapamycin, which reduces metabolic activity by blocking mTOR. Indeed, treating healthy cells with rapamycin increased the proliferation and survival of the neighboring melanoma cells.

While this last result is intriguing, rapamycin is currently the most effective drug for lifespan extension in mice [4]. Considering that mice die mostly of cancer, it seems that rapamycin’s effects on cancer risk are positive overall. However, the specific connection uncovered by the researchers deserves a closer look.