Proteasome Inhibition Enhances Lysosome-mediated Targeted Protein Degradation

Area of Science:

• Oncology
• Molecular Biology
• Cellular Stress Response

Background:

• Proteasome inhibitors are used for multiple myeloma and mantle cell lymphoma, but cancer cells develop resistance.
• Cancer cells activate Nuclear factor erythroid 2-related factor 1 (NRF1) to upregulate proteasome and autophagy genes, counteracting proteasome inhibition.
• NRF1-mediated adaptive autophagy reduces proteotoxic stress, diminishing proteasome inhibitor effectiveness.

Purpose of the Study:

• To investigate therapeutic strategies that exploit, rather than suppress, the adaptive autophagy response to proteasome inhibition.
• To design and evaluate an autophagy-targeting chimera (AUTAC) for selective degradation of the anti-apoptotic protein Mcl1.
• To determine if combining proteasome inhibition with Mcl1 AUTAC enhances cancer cell death.

Main Methods:

• Development of an autophagy-targeting chimera (AUTAC) compound for lysosomal degradation of Mcl1.
• Treatment of cancer cells with a combination of a proteasome inhibitor (carfilzomib) and Mcl1 AUTAC.
• Assessment of NRF1-dependent mechanisms and synergistic effects on cell death in wild-type and resistant cancer cell lines.

Main Results:

• Lysosome-mediated Mcl1 degradation by AUTAC was significantly amplified in the presence of proteasome inhibition.
• This amplification was dependent on the transcription factor NRF1.
• The combination of carfilzomib and Mcl1 AUTAC synergistically induced cell death in multiple myeloma and lung cancer cells, including resistant phenotypes.

Conclusions:

• Combining proteasome inhibitors with Mcl1 AUTAC represents a novel strategy to enhance cancer therapy by exploiting adaptive autophagy.
• This approach establishes a framework for amplifying lysosome-mediated targeted protein degradation for therapeutic benefit.
• The findings have broad potential applications in cancer therapeutics and other diseases involving protein homeostasis.