CRISPRi/a screens to identify modifiers of response to the bi-steric mTORC1 inhibitor RM-006

To identify strategies to enhance the utility of mTOR inhibitors we performed forward genetic screens with new bi-steric mTORC1 inhibitors. These screens show that mTORC1 inhibitor-mediated cytostasis leaves cells exquisitely dependent on the lipid peroxide scavenging enzyme GPX4.

Mechanistically, using unbiased gene activation screens, we demonstrate that mTORC1-dependent control of ferroptosis occurs, in part, through regulation of SCARB1 expression. Together, our work reaffirms combining mTORC1 with GPX4 inhibition as one of the most promising combinatorial approaches for mTOR-targeted cancer therapies and defines an HDL-dependent ferroptosis suppression system that is regulated by mTORC1 activity.