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

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.

Keywords: Apoptosis; Autophagy; Tumor metabolism; mTOR inhibitor; mTOR signaling pathway.

Fig. 1

The relationship between mTOR and tumors. Overactivation of mTORC1 can promote tumor formation, proliferation, and metastasis, while mTORC2 can regulate the expression of mTORC1 through the mTORC2/AKT/TSC/Rehb pathway. Pathway 1: The extracellular growth signals and intracellular LKB1 mutations activate mTORC1, which reduces the ubiquitination of histone H2A and H2A after DNA damage by phosphorylating RNF168. This can lead to damage to DNA repair and promote the formation of tumors. Pathway 2: The ubiquitination of Rheb reduces Rheb activity by promoting Rheb binding to TSC2. The down-regulation of Rehb reduces the activation of mTORC1, leading to the inhibition of tumor growth. Pathway 3: TRAF2 and Otud7B respectively regulate mTORC1/2 activity by up-regulating or down-regulating the ubiquitination level of G beta L of mTORC2. TRAF2 enhanced the activity of mTORC1 and inhibited the activity of mTORC2. Although down-regulation of mTORC2 expression inactivates the AKT/TSC/Rehb/mTORC1 pathway, overall mTORC1 activity is enhanced. However, Otud7B has the opposite effect on TRAF2. Pathway 4: Mutated Ras binds mTOR and MAPKAP1 of mTORC2 to promote mTORC2 expression. The up-regulation of mTORC2 promotes tumor proliferation through the AKT/TSC/Rehb/mTORC1 pathway. Pathway 5: Deletion of the PTEN gene induces the expression of B7-H1 to increase tumor progression and invasion. Pathway 6: The PI3K/PTEN/AKT/mTOR pathway is involved in the invasion and metastasis of liver cancer by up-regulating MMP-9

Fig. 2

Interaction between tumor metabolism and the mTOR signaling pathway. The mTOR pathway is closely related to tumor metabolism. Pathway 1: In bladder cancer, down-regulation of PKM2 expression reduces SREBP-1 expression through inactivated AKT/TSC/Rehb/mTORC1 pathway. The down-regulation of SREBP-1c inhibits FA generation by inhibiting FASN transcription, leading to the inhibition of tumor growth.). Pathway 2: Up-regulation of TEF in tumors activates the Ras/Erk/TSC/Rehb/mTORC1 pathway. Activation of this pathway will promote the uptake of nutrients by tumor cells to meet the needs of the rapid growth of tumors. Pathway 3: HCC can increase sphingomyelin and cardiolipin production by activating mTORC2. Large amounts of sphingomyelin and cardiolipin are used to assemble cell membranes, which also meet the needs of rapid tumor proliferation. Pathway 4: The accumulation of BCAA can promote the occurrence and development of tumors by activating mTORC1. Pathway 5: A2aR, which is highly expressed in gastric cancer, binds adenosine to activate the PI3K/AKT/mTORC1 pathway. Pathway 6: In breast cancer, FFAs promotes tumor proliferation and metastasis by activating the PI3K/AKT/mTORC1 pathway. Pathway 7: The PI3K/AKT/mTORC1/SREBP pathway promotes breast cancer proliferation by inducing new lipid synthesis