RPTOR independent companion of MTOR, complex 2 (RICTOR) is a gene that encodes the protein RICTOR (rapamycin-insensitive companion of mTOR). RICTOR is a member of the protein complex mTORC2 that functions in the regulation of actin organization, cell proliferation and survival. The mTORC2 is composed of mTOR, LST8, Deptor, RICTOR, Protor, and SIN1. The mTORC2 has PDK2 kinase activity and is responsible for AKT phosphorylation at Ser473 and its subsequent full activation. The mTORC2 appears to be upstream regulated by PI3K. RICTOR also carries mTOR-independent functions to modify cell morphology, migration and protein degradation.
Missense mutations, nonsense mutations, silent mutations, amplifications, and frameshift deletions and insertions have been observed in cancers such as breast cancer, endometrial cancer, intestinal cancer, lung cancer, and stomach cancer.
Patients with RICTOR amplification, especially when it is the sole targetable genomic alteration, may be appropriate candidate for trials with dual mTOR1/2 inhibitors.
Figure 1. Binding of a growth factor (e.g., EGF, HGF) to a receptor tyrosine kinase (RTK) activates the receptor. Insulin receptor substrate-1 (IRS-1) or an analogous adapter protein binds to the receptor tyrosine kinase. Phosphoinositide 3-kinase (PI3K) is composed of two subunits: p85 and p110. PI3K binds to IRS-1 and activates the enzymatic activity of the p110 subunit. Active PI3K binds to phosphatidylinositol 4, 5-bisphosphate (PIP2) in the cell membrane. PI3K initiates transphosphorylation from PIP2 to create PIP3. Phosphorylated PIP3 or PDK1 activate AKT. AKT is fully activated when its Thr308 and Ser473 are phosphorylated by PDK1 and mTORC2. The activation of AKT triggers downstream activation of gene transcription and promotes cell growth and survival. Specific nodes in the pathway that are therapeutically actionable are noted.
Suggested Citation: Cheng, H., C. Lovly, R. Perez-Soler. 2016. RICTOR. My Cancer Genome https://www.mycancergenome.org/content/disease/lung-cancer/rictor/?tab=0 (Updated January 4).
Last Updated: January 4, 2016