Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Mammalian target of rapamycin (mTOR) is a key regulator of cell growth, proliferation, and autophagy.
• Overactivation of mTOR signaling is implicated in various cancers.
• No activating mutations in mTOR itself have been previously identified in human cancer.

Purpose of the Study:

• To identify and characterize activating mutations in the mTOR kinase in human cancers.
• To investigate the functional consequences of these novel mTOR mutations on cellular processes.
• To assess the therapeutic implications of these mutations, particularly regarding sensitivity to mTOR inhibitors.

Main Methods:

• Bioinformatic analysis of human cancer genome databases to identify mTOR mutations.
• In vitro kinase assays using purified mTOR complexes with mutant forms.
• Cellular assays to assess proliferation, cell cycle progression, and response to nutrient starvation.
• Sensitivity assays to rapamycin and 1-butanol.

Main Results:

• Two novel activating point mutations in mTOR, S2215Y (large intestine adenocarcinoma) and R2505P (renal cell carcinoma), were identified.
• Mutant mTOR exhibited constitutive kinase activity, phosphorylating 4E-BP1 even under nutrient starvation.
• Cells expressing mutant mTOR showed increased S-phase population and resistance to amino-acid starvation-induced cell size reduction.
• Activated mutants remained sensitive to rapamycin but showed increased resistance to 1-butanol.

Conclusions:

• Activating mutations in mTOR can occur in human cancers, leading to constitutive signaling.
• These mutations promote cell proliferation and survival, contributing to tumorigenesis.
• The identification of these mutations has implications for targeted cancer therapies, particularly with mTOR inhibitors.