Targeting mTORC1 to promote ferroptosis and apoptosis in endometrial cancer with PI3K-Akt-mTOR pathway mutation

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Endometrial cancer (EC) is frequently driven by the PI3K-Akt-mTOR (PAM) pathway.
• Mechanistic target of rapamycin complex 1 (mTORC1) inhibitors have limited efficacy as single agents in EC.
• Ferroptosis, a form of regulated necrosis, is iron-dependent and involves lipid peroxidation.

Purpose of the Study:

• To investigate combining mTORC1 inhibition with ferroptosis induction to overcome resistance mechanisms in EC.
• To evaluate the effect of different mTORC1 inhibition types on ferroptosis sensitivity in EC cell lines.
• To assess the in vivo efficacy of combination therapy in EC xenograft models.

Main Methods:

• Evaluated catalytic, allosteric, and bi-steric mTORC1 inhibition on ferroptosis sensitivity in EC cell lines with varying PAM pathway mutational status.
• Tested in vivo efficacy of combination treatment in MFE296 xenograft models.
• Utilized GPX4 inhibition to induce ferroptosis.

Main Results:

• A catalytic and bi-steric mTORC1 inhibitor (RMC-6272) sensitized PAM pathway-activated EC cells to ferroptosis induced by GPX4 inhibition.
• mTORC1 inhibition induced apoptosis in PAM pathway-activated EC cells, demonstrating a multi-modal cell death response.
• Combination treatment with RMC-6272 and a GPX4 inhibitor (JKE-1674) significantly suppressed xenograft growth, with tumors showing both ferroptosis and apoptosis.

Conclusions:

• Dual targeting of mTORC1 and ferroptosis offers therapeutic potential for PAM pathway-activated EC.
• This combination strategy triggers multi-modal cell death, enhancing treatment outcomes.
• Findings have broader implications for other cancers with mTORC1 hyperactivation.