Just did a quick search, not finding references connecting TOR2 hyper activation with TOR1 suppression. Generally, Rapamycin suppresses both, much more so TOR1, and TOR2 only under chronic administration.
TOR2 hyper activation is indeed associated with various cancer lines, but Rapamycin clearly suppresses TOR2, and has been shown resoundingly to reduce cancer growth in various animal models.
4.2. Cancer.
Deregulation of mTORC2, particularly hyperactivation, has been commonly observed in many types of human cancers. Mutations and aberrant amplifications of mTORC2 core components are two main factors contributing to its hyperactivation. For example, mutations in the mTOR-FAT domain decrease mTOR binding to the inhibitor DEPTOR, thereby conferring the hyperactivation of both mTOR complexes [102]. In addition, Rictor has also been identified to be highly mutated [102] and abnormally overexpressed through genetic and epigenetic regulations [103] in a variety of cancer types. The exact functions of these abnormalities in tumorigenesis and treatment await identification. Nonetheless, mTORC2 regulates AGC kinase family proteins, such as Akt and PKC, for their stabilization and activity, which have important roles in the cell proliferation, survival, and migration, thereby having a crucial role in cancer [2]. In terms of metabolism, mTORC2 activation promotes glucose uptake, facilitates glycolysis, and inhibits oxidative phosphorylation, which may contribute greatly to the alter- ation of glucose metabolism in cancer cells, known as the Warburg Effect, conferring to a high rate of cell prolifera- tion [71, 79]. Furthermore, mTORC2-mediated lipogenesis is identified to promote hepatocellular carcinoma, particularly by stimulating sphingolipid and glycerophospholipid synthesis, which fuels cancer cell growth and energy production [104].
In addition, Rapamycin derivatives have been applied to cancer treatment in clinical trials with limited efficiency, which is thought to be due to the limitation to inhibit mTORC2 [2]. As such, the second-generation ATP- competitive inhibitors against mTOR kinase have entered clinical trials [105]. These mTOR kinase inhibitors show greater inhibitory effects on both complexes and are more effective in inhibiting cancer cell growth [106]. Moreover, dual mTOR/PI3K kinase inhibitors have been developed in order to fully suppress Akt and 4EBP1 activation [107]. Recently, selective inhibition of mTORC2 signaling by a nanoparticle-based RNAi therapy showed being able to effec- tively block breast cancer cell growth and survival [108]. All these suggest that mTORC2 might be a good therapeutic target for cancer treatment.
