• What is RICTOR?
  • RICTOR in Lung Cancer
  • RICTOR Amplification
  • Clinical Trials

RICTOR

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.

PI3K/mTOR Pathway

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.

Related Pathways

Contributors: Haiying Cheng, M.D., Ph.D., Christine M. Lovly, M.D., Ph.D., Roman Perez-Soler, M.D.

Suggested Citation: Cheng, H., C. Lovly, R. Perez-Soler. 2016. RICTOR. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/rictor/?tab=0 (Updated January 4).

Last Updated: January 4, 2016

RICTOR in Lung Cancer

Genomic alterations in RICTOR are found in 10.9–14.3% lung adenocarcinoma cases and 10.6–16.9% of lung squamous cell carcinoma (c-Bio). The vast majority of RICTOR alterations in NSCLC are amplifications though missense mutations are spread throughout the gene (c-Bio). RICTOR amplifications can be detected clinically by next generation sequencing or fluorescence in situ hybridization (FISH).

In a review of 1070 lung cancer samples assayed by FoundationOne® next generation sequencing, RICTOR amplification was the sole actionable target alteration in 11% of RICTOR-amplified cases, while 34% had additional alterations in other genes in the PI3K/AKT/mTOR pathway (Cheng et al. 2015). Further, 26% had additional alterations in EGFR and 14% had additional alterations in KRAS (Cheng et al. 2015). RICTOR amplification was also found in 14.6% of small cell lung cancer cases (Cheng et al. 2015).

Contributors: Haiying Cheng, M.D., Ph.D., Christine M. Lovly, M.D., Ph.D., Roman Perez-Soler, M.D.

Suggested Citation: Cheng, H., C. Lovly, R. Perez-Soler. 2016. RICTOR in Lung Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/rictor/ (Updated January 4).

Last Updated: January 4, 2016

RICTOR Amplification in Lung Cancer

Properties
Location of mutation Focal amplification on chromosome 5p13
Frequency of RICTOR amplification in NSCLC 8.4–10.3% in adenocarcinoma (Cheng et al. 2015)
7.4–15.8% in squamous cell carcinoma (Cheng et al. 2015)
8.7% in large cell neuroendocrine carcinoma(Cheng et al. 2015)
Implications for Targeted Therapeutics
PI3K inhibitors Unknown at this timea
TORC1/2 inhibitors Confers increased sensitivitya

RICTOR amplification was detected in a case study of a very young patient with lung adenocarcinoma. This was the only potentially actionable genomic alteration detected in the patient’s tumor sample using a next generation sequencing assay. Additionally, several phosphorylated targets of the mTORC2-RICTOR complex and of the mTORC1 complex were overexpressed in the index patient, suggesting hyperactivity of mTORC2-RICTOR as well as mTORC1 (Cheng et al. 2015).

aRICTOR amplification is associated in preclinical models with sensitivity to clinically achievable doses of PI3K/AKT/mTOR pathway inhibitors, with the most potent agents tested being dual catalytic mTOR1/2 inhibitors. In addition, a modest association between RICTOR amplification and sensitivities to mTOR1/2 inhibitors was observed in vitro (Cheng et al. 2015).

Reference Study Type Diagnosis Alteration Line of Treatment Treatment Best Response Duration of Response
Cheng et al. 2015 Case report Lung adenocarcinoma RICTOR amplification third CC223 Stable Disease 12 months
Fifth MLN0128 Stable Disease 6 months

Contributors: Haiying Cheng, M.D., Ph.D., Christine M. Lovly, M.D., Ph.D., Roman Perez-Soler, M.D.

Suggested Citation: Cheng, H., C. Lovly, R. Perez-Soler. 2016. RICTOR Amplification in Lung Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/rictor/340/ (Updated January 4).

Last Updated: January 4, 2016

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