Title:Targeted Inhibition of Rictor/mTORC2 in Cancer Treatment: A New Era after Rapamycin
Volume: 16
Issue: 4
Author(s): Zhipeng Zou, Juan Chen, Jun Yang and Xiaochun Bai
Affiliation:
Keywords:
Cancer, mSIN1, mTORC2, mTOR inhibitors, rapamycin, rictor.
Abstract: The evolutionarily conserved mechanistic target of rapamycin (mTOR) forms two
functionally distinct complexes, mTORC1 and mTORC2. mTORC1, consisting of mTOR, raptor, and
mLST8 (GβL), is sensitive to rapamycin and thought to control autonomous cell growth in response
to nutrient availability and growth factors. mTORC2, containing the core components mTOR,
mLST8, Rictor, mSIN1, and Protor1/2 is largely insensitive to 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. Although preclinical and
clinical studies of ATP-competitive mTOR inhibitors that target both mTORC1 and mTORC2 have shown greater
effectiveness than rapalogs for cancer treatment, the mTORC1 inhibition-induced negative feedback activation of PI3-
K/PDK1 and Akt (Thr308) may be sufficient to promote cell survival. 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.
