Journal: Cell discovery
This study identifies a novel mechanism behind multidrug resistance in cancer, involving the direct binding of anticancer drugs to newly synthesized proteins, especially mitochondrial proteins. This binding causes protein damage and cytotoxicity.
The protein damage triggers mitochondrial reactive oxygen species production, creating a feedback loop that amplifies harm.
In response, cancer cells activate a Protein Damage Response (PDR), which includes:
- Protein ubiquitination
- Enhanced clearance through the proteasome system
Elevated proteasome activity was observed in advanced, drug-resistant metastatic breast and colon cancer patients.
The authors developed a sensitive assay to detect proteasome levels, enabling patient stratification for tailored therapies.
Using tumor slice cultures and a clinical trial, they demonstrated that proteasome inhibitors can effectively overcome multidrug resistance in patients with high proteasome activity.