mTORC1 activity suppresses ferroptosis through a SCARB1-dependent HDL-tocopherol uptake pathway

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Aberrant PI3K/AKT/mTOR signaling is common in cancer.
• mTOR inhibitors show limited success as single agents.
• Strategies to enhance mTOR inhibitor efficacy are needed.

Purpose of the Study:

• To identify strategies to enhance the utility of third-generation bi-steric mTORC1 inhibitors.
• To elucidate mechanisms of cancer cell response to mTORC1 inhibition.

Main Methods:

• Genome-scale CRISPR interference and activation chemogenomics screens.
• Cellular assays to assess ferroptosis and lipid peroxide scavenging.
• Investigated the role of HDL, SCARB1, and vitamin E in ferroptosis.

Main Results:

• mTORC1 inhibition induces cancer cell dependency on GPX4 for survival.
• mTORC1 regulates ferroptosis partly through SCARB1 expression.
• HDL-SCARB1 interaction suppresses ferroptosis via vitamin E delivery.

Conclusions:

• Combining mTORC1 and GPX4 inhibition is a promising cancer therapy strategy.
• The HDL-SCARB1 system is a novel mTORC1-regulated ferroptosis-suppression mechanism.