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Review
. 2022 Sep 15;22(1):284.
doi: 10.1186/s12935-022-02706-8.

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

Eunus S Ali  1   2   3 , Kangkana Mitra  4 , Shamima Akter  5 , Sarker Ramproshad  6 , Banani Mondal  6 , Ishaq N Khan  7 , Muhammad Torequl Islam  8 , Javad Sharifi-Rad  9 , Daniela Calina  10 , William C Cho  11
Affiliations
Review

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

Eunus S Ali et al. Cancer Cell Int. .

Abstract

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.

Keywords: Cancer; Rapamycin; Targeted therapy; mTOR inhibitors; mTOR pathway; mTORC1; mTORC2.

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Conflict of interest statement

Authors wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.

Figures

Fig. 1
Fig. 1
Schematic representation of different domains of mTOR and the inhibitors where those binds
Fig. 2
Fig. 2
Constituent proteins of mTORC1 and mTORC2. A a central signaling molecule that is the mammalian target of rapamycin (mTOR) serves as a core constituent to form a distinctive complex with other molecules DEPTOR, PRAS40, mLST8 and Raptor, resulting in the formation of the mTORC1 complex, while the B mTOR with other five proteins DEPTOR, mSin1, Mlst8, Rictor and Protor forms the mTORC2 complex. Both the distinct protein complexes regulate several cellular mechanisms
Fig. 3
Fig. 3
Proposed origin of potency and selectivity of pyrazolopyrimidine analogs for mTOR
Fig. 4
Fig. 4
Chemical structures of mTOR inhibitors
Fig. 5
Fig. 5
The mTORC1/2 signaling pathway and its inhibitors in clinical trials
Fig. 6
Fig. 6
Generation of RapaLinks. Linking an mTOR kinase inhibitor INK-128 (or MLN0128) to rapamycin led to RapaLinks which exhibited improved efficacy in tumor-bearing mice than each of the constituents alone
See this image and copyright information in PMC

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