Abstract
AIMS: Endometrial cancer (EC) is often driven by hyperactivation of the PI3K-Akt-mTOR (PAM) pathway due to mutations in PTEN and/or PI3K genes. While mechanistic target of rapamycin complex 1 (mTORC1) inhibitors show limited efficacy as single agents in EC, previous studies suggest that they may sensitize the PAM-mutant cancer cells to ferroptosis, a regulated form of necrosis dependent on iron-catalyzed lipid peroxidation. We investigated whether combining mTORC1 inhibition with ferroptosis induction could overcome resistance mechanisms and improve therapeutic outcomes in EC. METHODS: We evaluated the effect of catalytic, allosteric, and bi-steric mTORC1 inhibition on ferroptosis sensitivity in EC cell lines with different PAM pathway mutational statuses. In vivo efficacy of the combinational treatment was tested in MFE296 xenograft models. RESULTS: The catalytic and bi-steric mTORC1 inhibitor RMC-6272 sensitized PAM pathway-activated EC cells to ferroptosis induced by GPX4 inhibition, while EC cells without PAM pathway activation were intrinsically sensitive to ferroptosis. Further, mTORC1 inhibition also induced apoptosis in PAM pathway-activated EC cells, indicating a multi-modal cell death response. In vivo, combination treatment with RMC-6272 and the GPX4 inhibitor JKE-1674 significantly suppressed xenograft growth, with evidence of both ferroptosis and apoptosis in tumors. CONCLUSION: Our study highlights the therapeutic potential of dual targeting of mTORC1 and ferroptosis to trigger multi-modal cell death in PAM pathway-activated EC, with broader implications for other cancers exhibiting mTORC1 hyperactivation.