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Proteasome Inhibition as a Cancer Type-Specific Off-Target Effect of Everolimus in Cancer Cells

Anna S Vorobeva1, Elizaveta M Kazakova1, Leyla A Garibova1

  • 1Talrose Institute for Energy Problems of Chemical Physics, Semenov Federal Research Center for Chemical Physics, Russian Academy of Sciences, Moscow, 119334, Russia.

Biochemistry. Biokhimiia
|March 17, 2026
PubMed

Insights

Everolimus, an mTORC1 inhibitor, was found to inhibit the 20S proteasome in lung and colon cancer cells, but not breast cancer cells. This study used proteomics and cell assays to explore its mechanism of action.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Pharmacology

Background:

  • Everolimus is an mTORC1 inhibitor with potential effects on proteasome activity, similar to bortezomib.
  • Understanding the comprehensive mechanism of action of everolimus is crucial for its therapeutic application.

Purpose of the Study:

  • To investigate the secondary targets of everolimus, specifically its effect on proteasome activity.
  • To elucidate the mechanism of action of everolimus in various cancer cell lines using advanced proteomic techniques.

Main Methods:

  • Ultrafast expression proteomics was utilized to analyze proteomes.
  • Cell viability and proteasome activity assays were performed.
  • In silico modeling was employed to predict drug-target interactions.

Main Results:

  • Everolimus demonstrated 20S proteasome inhibition in lung (A549) and colon (HCT116) cancer cells.
  • No significant proteasome inhibition by everolimus was observed in breast cancer cells (MCF-7).
  • An in silico model suggested an allosteric mechanism for everolimus-induced proteasome inhibition.

Conclusions:

  • Everolimus exhibits cancer cell-specific proteasome inhibition, impacting its therapeutic potential.
  • The findings provide insights into the off-target effects of everolimus and suggest novel therapeutic strategies.
Keywords:
bortezomibeverolimusproteasome inhibitorsprotein expressionultrafast proteomics

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