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Published on: May 10, 2022
Therapeutic implications of mitochondrial stress-induced proteasome inhibitor resistance in multiple myeloma
Aditi Sharma1, Remya Nair1, Abhinav Achreja2,3
1Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA, USA.
Abstract:
The connections between metabolic state and therapy resistance in multiple myeloma (MM) are poorly understood. We previously reported that electron transport chain (ETC) suppression promotes sensitivity to the BCL-2 antagonist venetoclax. Here, we show that ETC suppression promotes resistance to proteasome inhibitors (PIs). Interrogation of ETC-suppressed MM reveals integrated stress response-dependent suppression of protein translation and ubiquitination, leading to PI resistance. ETC and protein translation gene expression signatures from the CoMMpass trial are down-regulated in patients with poor outcome and relapse, corroborating our in vitro findings. ETC-suppressed MM exhibits up-regulation of the cystine-glutamate antiporter SLC7A11, and analysis of patient single-cell RNA-seq shows that clusters with low ETC gene expression correlate with higher SLC7A11 expression. Furthermore, erastin or venetoclax treatment diminishes mitochondrial stress-induced PI resistance. In sum, our work demonstrates that mitochondrial stress promotes PI resistance and underscores the need for implementing combinatorial regimens in MM cognizant of mitochondrial metabolic state.
Insights
Electron transport chain suppression causes resistance to proteasome inhibitors in multiple myeloma by affecting protein translation. Targeting mitochondrial stress may improve treatment strategies for this cancer.
Area of Science:
- Oncology
- Molecular Biology
- Metabolism
Background:
- The relationship between metabolic status and treatment resistance in multiple myeloma (MM) is not well understood.
- Previous research indicated that suppressing the electron transport chain (ETC) increases sensitivity to venetoclax, a BCL-2 inhibitor.
Purpose of the Study:
- To investigate the impact of ETC suppression on resistance to proteasome inhibitors (PIs) in multiple myeloma.
- To elucidate the molecular mechanisms underlying ETC suppression-induced PI resistance.
- To explore the role of SLC7A11 and mitochondrial stress in this resistance.
Main Methods:
- In vitro studies of ETC-suppressed multiple myeloma models.
- Analysis of gene expression signatures from the CoMMpass patient trial.
- Single-cell RNA sequencing of patient samples.
- Treatment with erastin or venetoclax.
Main Results:
- ETC suppression leads to resistance to proteasome inhibitors (PIs) in multiple myeloma.
- This resistance is mediated by integrated stress response-dependent suppression of protein translation and ubiquitination.
- Down-regulation of ETC and protein translation gene signatures correlates with poor outcomes and relapse in MM patients.
- ETC-suppressed MM shows increased expression of the cystine-glutamate antiporter SLC7A11.
- Erastin or venetoclax treatment reduced mitochondrial stress-induced PI resistance.
Conclusions:
- Mitochondrial stress, induced by ETC suppression, promotes resistance to proteasome inhibitors in multiple myeloma.
- Therapeutic strategies for MM should consider the metabolic state, particularly mitochondrial function, and explore combinatorial regimens.
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