Suppressing protein damage response to overcome multidrug resistance in cancer therapy

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Multidrug resistance (MDR) is a major challenge in cancer therapy.
• The regulatory mechanisms underlying MDR are not fully understood.
• Anticancer drugs can cause off-target protein damage, contributing to cytotoxicity.

Purpose of the Study:

• To investigate the mechanisms of anticancer drug-induced protein damage.
• To identify cellular responses to protein damage, termed the Protein Damage Response (PDR).
• To explore the role of proteasome activity in MDR and develop strategies to overcome it.

Main Methods:

• Analysis of drug-induced protein binding and subsequent cellular damage.
• Characterization of the Protein Damage Response (PDR) pathway, including ubiquitination and proteasome degradation.
• Development of a kit to detect proteasome levels in patient samples.
• Validation of proteasome inhibitors in 3D tumor slice cultures and a clinical trial.

Main Results:

• Anticancer drugs bind to newly synthesized proteins, causing damage, particularly to mitochondrial proteins.
• This initial damage triggers a positive feedback loop involving reactive oxygen species and leads to the PDR.
• Elevated proteasome activity is observed in drug-resistant metastatic breast and colon cancers.
• A proteasome detection kit identified patients with high proteasome activity.
• Proteasome inhibitors reversed MDR in patients with high proteasome activity.

Conclusions:

• Drug-induced protein damage and the subsequent PDR are key mechanisms in cancer therapy resistance.
• Proteasome activity is a predictive biomarker for MDR.
• Targeting proteasome activity with inhibitors offers a promising strategy to overcome MDR in specific cancer patient populations.