MTOR Signaling in Cancer and mTOR Inhibitors in Solid Tumor Targeting Therapy.

Xiaoyi Li,Jinhua Zhang,Tian Tian

doi:10.3390/ijms20030755

Xiaoyi Li, Jinhua Zhang + Show 1 more

Open Access

https://doi.org/10.3390/ijms20030755

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Abstract

The mammalian or mechanistic target of rapamycin (mTOR) pathway plays a crucial role in regulation of cell survival, metabolism, growth and protein synthesis in response to upstream signals in both normal physiological and pathological conditions, especially in cancer. Aberrant mTOR signaling resulting from genetic alterations from different levels of the signal cascade is commonly observed in various types of cancers. Upon hyperactivation, mTOR signaling promotes cell proliferation and metabolism that contribute to tumor initiation and progression. In addition, mTOR also negatively regulates autophagy via different ways. We discuss mTOR signaling and its key upstream and downstream factors, the specific genetic changes in the mTOR pathway and the inhibitors of mTOR applied as therapeutic strategies in eight solid tumors. Although monotherapy and combination therapy with mTOR inhibitors have been extensively applied in preclinical and clinical trials in various cancer types, innovative therapies with better efficacy and less drug resistance are still in great need, and new biomarkers and deep sequencing technologies will facilitate these mTOR targeting drugs benefit the cancer patients in personalized therapy.

Highlights

The mammalian or mechanistic target of rapamycin is a serine/threonine kinase that acts through two structurally and functionally distinct protein complexes, mTOR complex 1 and mTOR complex 2, to sense and integrate multiple intracellular and environmental signals [1,2]. mTOR signaling is generally involved in regulating cell survival, cell growth, cell metabolism, protein synthesis and autophagy, as well as homeostasis [3]
MTORC1 and mTOR complex 2 (mTORC2) have differing subcellular localization binding with their own respective, specific subunits, which determine their distinct functions and independent regulations. mTOR complex 1 (mTORC1) is associated with endosomal and lysosomal membranes, where it interacts with its effectors. mTORC2 is affiliated with the plasma membrane, as well as ribosomal membranes, where it binds with its key substracts, AGC family kinases (subgroup of Ser/Thr protein kinases named after 3 representative families, the cAMP-dependent protein kinase (PKA), the cGMP-dependent protein kinase (PKG) and the protein kinase C (PKC) families), such as serum glucose kinase (SGK) isoforms and protein kinase C (PKC), which are essential for mTORC2 activation [20]
In the following parts of our review, we focus on the alterations of mTOR signaling in eight different types of solid tumors and applications of various mTOR inhibitors in therapeutic strategies in these specific tumors

Summary

Introduction

The mammalian or mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that acts through two structurally and functionally distinct protein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), to sense and integrate multiple intracellular and environmental signals [1,2]. mTOR signaling is generally involved in regulating cell survival, cell growth, cell metabolism, protein synthesis and autophagy, as well as homeostasis [3]. MTORC1 and mTORC2 are different in the aspects of rapamycin sensitivity, specific binding components, subcellular localization, downstream substrates, and regulation [12]. MTORC2 is affiliated with the plasma membrane, as well as ribosomal membranes, where it binds with its key substracts, AGC family kinases (subgroup of Ser/Thr protein kinases named after 3 representative families, the cAMP-dependent protein kinase (PKA), the cGMP-dependent protein kinase (PKG) and the protein kinase C (PKC) families), such as serum glucose kinase (SGK) isoforms and protein kinase C (PKC), which are essential for mTORC2 activation [20] Both mTORC1 and mTORC2 play significant and differing roles in a variety of intracellular processes.

Signaling of mTORC1

Signaling of mTORC2

Lung Cancer

Breast Cancer

Findings

Discussions and Future Prospects