Seems we know far less about mTOR2 than mTOR1, yet we seem to ascribe all the benefits of “Rapamycin longevity”, namely, the default chronically-daily-prolonged treatment-cancer mice model (unlike what us humans are doing), to mTOR1? But this is most definitely not true.
The Enigma of Rapamycin Dosage
“Rapamycin is a natural product that inhibits mTOR with high specificity. However, its efficacy varies by dose in several contexts. First, different doses of rapamycin are needed to suppress mTOR in different cell lines; second, different doses of rapamycin are needed to suppress the phosphorylation of different mTOR substrates; and third, there is a differential sensitivity of the two mTOR complexes mTORC1 and mTORC2 to rapamycin”
Targeted Inhibition of Rictor/mTORC2 in Cancer Treatment: A New Era after Rapamycin
“mTORC2 specifically senses growth factors and regulates cell proliferation, metabolism, actin rearrangement, and survival. Dysregulation of mTOR signaling often occurs in a variety of human malignant diseases, rendering it a crucial and validated target in cancer treatment. However, the effectiveness of rapamycin as single-agent therapy is suppressed, in part, by the numerous strong mTORC1-dependent negative feedback loops. Recent cancer biology studies indicated that mTORC2 is a promising target, since its activity is essential for the development of a number of cancers. These studies provide a rationale for developing inhibitors specifically targeting mTORC2, which do not perturb the mTORC1- dependent negative feedback loops and have a more acceptable therapeutic window. This review summarizes the present understanding of mTORC2 signaling and functions, especially tumorigenic functions, highlighting the current status and future perspectives for targeting mTORC2 in cancer treatment”
mTORC1 and mTORC2 in cancer and the tumor microenvironment
“While mTORC1 signaling has been extensively studied in cancer, recent discoveries indicate a subset of human cancers harboring amplifications in mTORC2-specific genes as the only actionable genomic alterations, suggesting a distinct role for mTORC2 in cancer as well mTORC2 in the center of cancer metabolic reprogramming”
“Here we review the recently identified central regulatory role for mTORC2, a downstream effector of many cancer-causing mutations, in metabolic reprogramming and cancer drug resistance.”
mTORC2 Promotes Tumorigenesis via Lipid Synthesis
https://www.cell.com/cancer-cell/pdfExtended/S1535-6108(17)30514-7
“mTORC2 promotes de novo fatty acid and lipid synthesis. This pathway is elevated in human liver cancer and drives hepatosteatosis and liver cancer in mice, whereas its inhibition or deletion of Rictor reduces mouse tumors, suggesting this pathway as a therapeutic target in liver cancer.”
