Targeting mTOR for cancer therapy

Hui Hua,Qingbin Kong,Jiao Wang,Hongying Zhang,Ting Luo,Yangfu Jiang

doi:10.1186/s13045-019-0754-1

Abstract

Mechanistic target of rapamycin (mTOR) is a protein kinase regulating cell growth, survival, metabolism, and immunity. mTOR is usually assembled into several complexes such as mTOR complex 1/2 (mTORC1/2). In cooperation with raptor, rictor, LST8, and mSin1, key components in mTORC1 or mTORC2, mTOR catalyzes the phosphorylation of multiple targets such as ribosomal protein S6 kinase β-1 (S6K1), eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), Akt, protein kinase C (PKC), and type-I insulin-like growth factor receptor (IGF-IR), thereby regulating protein synthesis, nutrients metabolism, growth factor signaling, cell growth, and migration. Activation of mTOR promotes tumor growth and metastasis. Many mTOR inhibitors have been developed to treat cancer. While some of the mTOR inhibitors have been approved to treat human cancer, more mTOR inhibitors are being evaluated in clinical trials. Here, we update recent advances in exploring mTOR signaling and the development of mTOR inhibitors for cancer therapy. In addition, we discuss the mechanisms underlying the resistance to mTOR inhibitors in cancer cells.

Highlights

The mechanistic target of rapamycin is a dualspecificity protein kinase phosphorylating serine/threonine as well as tyrosine residues [1]
The identification of the critical roles of mechanistic target of rapamycin (mTOR) and its regulators in tumorigenesis has driven the development of the ever-growing list of mTOR inhibitors
While some of the mTOR inhibitors have been approved to treat cancer patients, more mTOR inhibitors are under check to fulfill their promise for cancer therapy

Summary

Introduction

The mechanistic target of rapamycin (mTOR) is a dualspecificity protein kinase phosphorylating serine/threonine as well as tyrosine residues [1]. Inhibition of mTORC1 may lead to feedback activation of IGF-IR and Akt, which compromises the anti-cancer effect of rapalogs [1]. Combined inhibition of wee1, a protein kinase that regulates the G2 checkpoint in the cell cycle, with mTOR inhibition may selectively treat RAS-mutated cancer [174].

Results

Conclusion