Targeting the MYC oncogene with a selective bi-steric mTORC1 inhibitor elicits tumor regression in MYC-driven cancers

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• The MYC oncogene drives numerous human cancers.
• Mammalian target of rapamycin complex 1 (mTORC1) regulates MYC translation via 4EBP1 and S6K.
• Existing mTORC1-selective inhibitors are ineffective against MYC, while nonselective inhibitors have tolerability and immunosuppression issues.

Purpose of the Study:

• To develop novel agents targeting mTORC1 for effective MYC suppression.
• To evaluate the anti-tumor efficacy and immune-modulating effects of these new inhibitors.

Main Methods:

• Introduction of bi-steric mTORC1-selective inhibitors, including RMC-5552.
• Assessment of 4EBP1 reactivation and MYC protein level reduction.
• Evaluation in human patient-derived xenografts with MYC amplification.
• Testing in combination with immune checkpoint blockade.

Main Results:

• Bi-steric inhibitors potently reactivate 4EBP1 and decrease MYC protein levels.
• RMC-5552 demonstrated anti-tumor activity in xenograft models and reduced in vivo MYC.
• These inhibitors suppressed MYC signaling, leading to tumor growth inhibition via direct and immune-mediated effects.
• Combination therapy with immune checkpoint blockade resulted in tumor regression.

Conclusions:

• Bi-steric mTORC1-selective inhibitors represent a novel therapeutic strategy for MYC-driven cancers.
• These agents effectively suppress MYC and activate anti-tumor immunity.
• The findings support the clinical development of RMC-5552 and similar compounds, particularly in combination therapies.