A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• The PI3K-AKT-mTOR signaling pathway is crucial in cell growth and frequently altered in cancer.
• Mutations in MTOR, the gene encoding mTOR kinase, are less understood compared to other pathway components.

Purpose of the Study:

• To comprehensively catalog mutations in the MTOR gene within human cancers.
• To characterize the functional impact of identified MTOR mutations on pathway activity and cancer cell behavior.

Main Methods:

• Analysis of publicly available tumor genome sequencing data.
• Functional assays to assess mTOR complex assembly, DEPTOR binding, and signaling pathway activation.
• Evaluation of cancer cell line sensitivity to rapamycin in vitro and in vivo.

Main Results:

• Identified 33 novel MTOR mutations leading to pathway hyperactivation, clustering in specific regions.
• Mutations affect DEPTOR binding but not mTOR complex assembly.
• Cells with activating MTOR mutations show altered nutrient sensitivity but increased dependency on the mTOR pathway.

Conclusions:

• Discovered a set of activating MTOR mutations prevalent in various cancers, notably kidney cancer.
• Activating MTOR mutations confer sensitivity to mTOR inhibitors like rapamycin, suggesting therapeutic potential.