ETV7 is an essential component of a rapamycin-insensitive mTOR complex in cancer

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• The mechanistic target of rapamycin (mTOR) pathway is crucial for cell growth and frequently deregulated in cancer.
• Rapamycin, an mTOR inhibitor, has limited efficacy due to tumor resistance.
• Existing mTOR complexes (mTORC1 and mTORC2) do not fully explain this resistance.

Purpose of the Study:

• To investigate the mechanisms underlying rapamycin resistance in human cancers.
• To identify novel mTOR complexes involved in cancer progression.
• To explore new therapeutic targets for cancer treatment.

Main Methods:

• Investigated the role of the ETS transcription factor ETV7 in mTOR complex formation.
• Utilized cell lines and a rhabdomyosarcoma mouse model.
• Analyzed mTOR complex activity and its impact on tumor growth and drug sensitivity.

Main Results:

• Identified a novel mTOR complex, mTORC3, assembled by ETV7.
• mTORC3 is independent of ETV7's transcriptional activity and exhibits unique mTORC1/2 activity.
• mTORC3 is frequently activated in human cancers and contributes to rapamycin resistance.
• Loss of mTORC3 renders tumor cells sensitive to rapamycin.
• ETV7-induced mTORC3 accelerates tumor onset and promotes tumor penetrance in a mouse model.

Conclusions:

• Discovery of mTORC3 represents a paradigm shift in understanding mTOR signaling in cancer.
• mTORC3 is a key driver of tumorigenesis and rapamycin resistance.
• mTORC3 is a promising novel therapeutic target for anticancer drug development.