MTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges

Hongmei Li,Tao Tao,Zhilin Zou,Xiao Zhu

doi:10.1186/s13578-020-00396-1

Abstract

Mammalian target of rapamycin (mTOR) regulates cell proliferation, autophagy, and apoptosis by participating in multiple signaling pathways in the body. Studies have shown that the mTOR signaling pathway is also associated with cancer, arthritis, insulin resistance, osteoporosis, and other diseases. The mTOR signaling pathway, which is often activated in tumors, not only regulates gene transcription and protein synthesis to regulate cell proliferation and immune cell differentiation but also plays an important role in tumor metabolism. Therefore, the mTOR signaling pathway is a hot target in anti-tumor therapy research. In recent years, a variety of newly discovered mTOR inhibitors have entered clinical studies, and a variety of drugs have been proven to have high activity in combination with mTOR inhibitors. The purpose of this review is to introduce the role of mTOR signaling pathway on apoptosis, autophagy, growth, and metabolism of tumor cells, and to introduce the research progress of mTOR inhibitors in the tumor field.

Highlights

The Mammalian target of rapamycin (mTOR) forms two structurally and functionally distinct complexes called the mammalian target of rapamycin complex 1 and mammalian target of rapamycin complex 2. mTORC1 is comprised of mTOR, raptor, GβL and deptor, while mTORC2 is composed of mTOR, Rictor, GβL, PRR5, deptor, and SIN1. mTORC1 integrates signals from multiple growth factors, nutrients, and energy supply to promote cell growth when energy is sufficient and catabolism when the body is hungry. mTORC1 mainly regulates cell growth and metabolism, while mTORC2 mainly controls cell proliferation and survival [1]
The mTOR signaling pathway is closely related to tumors, and it is closely related to its cell growth, metabolism, apoptosis and autophagy [47, 81]
The mTOR signaling pathway can affect gene transcription and protein synthesis to regulate cell growth and proliferation, affect the immune cell differentiation to participate in immune regulation, and play an important role in tumor metabolism

Summary

Introduction

The mTOR forms two structurally and functionally distinct complexes called the mammalian target of rapamycin complex 1 (mTORC1) and mammalian target of rapamycin complex 2 (mTORC2). mTORC1 is comprised of mTOR, raptor, GβL and deptor, while mTORC2 is composed of mTOR, Rictor, GβL, PRR5, deptor, and SIN1. mTORC1 integrates signals from multiple growth factors, nutrients, and energy supply to promote cell growth when energy is sufficient and catabolism when the body is hungry. mTORC1 mainly regulates cell growth and metabolism, while mTORC2 mainly controls cell proliferation and survival [1]. The PI3K/ PTEN/Akt/mTOR pathway activated is involved in tumor invasion and metastasis by up-regulating matrix metallopeptidase 9 (MMP-9) [13]. The PI3K/ Akt/mTOR signaling pathway has been found to control the proliferation and survival of colon cancer stem cells (CCSC). Wang et al [17] demonstrated that OTU deubiquitinase 7B (OTUD7B) reduced ubiquitination level of GβL to prevent GβL from interacting with SIN1, leading to activation of mTORC2/ AKT signaling pathway and down-regulation of mTORC1 expression. This partially activates AKT oncogenic signaling and promotes tumorigenesis. Kovalski et al [18] proved that Ras mutations can bind to mTOR of mTORC2 and mitogen-activated protein kinase-associated protein 1 (MAPKAP1) to promote the activity of mTORC2 kinase, initiating downstream proliferative cell cycle transcription programs

Objectives

Conclusion