Cooperative Targets of Combined mTOR/HDAC Inhibition Promote MYC Degradation

Area of Science:

• Oncology
• Molecular Pharmacology
• Cancer Therapeutics

Background:

• Effective cancer treatment often necessitates combination therapies with molecularly targeted agents.
• mTOR inhibitors (rapamycin) and HDAC inhibitors (MS-275/entinostat) have demonstrated efficacy in limiting tumor growth individually.

Purpose of the Study:

• To elucidate the cooperative mechanisms underlying the synergistic action of combining mTOR inhibitors and HDAC inhibitors.
• To identify a clinically actionable strategy for inhibiting MYC/E2F activity and tumor cell growth.

Main Methods:

• Synergistic effects of the drug combination were evaluated across over 60 human cancer cell lines.
• Preclinical models, including a breast cancer patient-derived xenograft and a BCL-XL plasmacytoma mouse model, were used to assess in vivo responses.
• Pharmacodynamic analysis of gene expression changes, upstream regulator analysis, and MYC half-life studies were conducted.

Main Results:

• The combination treatment exhibited synergistic effects (CI<1) in more than 60 cancer cell lines and enhanced responses in preclinical models, significantly extending survival in mice with plasma cell tumors.
• A set of 37 genes (34 downregulated, 3 upregulated) were identified as pharmacodynamically affected by the combination, correlating with prognostic markers in myeloma patients.
• The drug combination significantly inhibited the MYC/E2F axis, reduced MYC half-life, and induced MYC degradation, with MYC mutations conferring refractoriness to the treatment.

Conclusions:

• Integrative approaches to understanding drug synergy revealed that the combination of mTOR and HDAC inhibitors is a clinically actionable strategy.
• This combination effectively inhibits MYC/E2F activity, leading to reduced tumor cell growth and improved outcomes in preclinical settings.
• The findings highlight the importance of targeting the MYC/E2F axis for cancer therapy.