2. Academic Validation
  3. Therapeutic implications of mitochondrial stress-induced proteasome inhibitor resistance in multiple myeloma

Therapeutic implications of mitochondrial stress-induced proteasome inhibitor resistance in multiple myeloma

  • Sci Adv. 2022 Sep 30;8(39):eabq5575. doi: 10.1126/sciadv.abq5575.
Aditi Sharma 1,  Remya Nair 1,  Abhinav Achreja 2 3,  Anjali Mittal 3 4,  Pulkit Gupta 1,  Kamakshi Balakrishnan 1,  Claudia L Edgar 1,  Olamide Animasahun 3 4,  Bhakti Dwivedi 5,  Benjamin G Barwick 1,  Vikas A Gupta 1,  Shannon M Matulis 1,  Manoj Bhasin 5,  Sagar Lonial 1,  Ajay K Nooka 1,  Arun P Wiita 6,  Lawrence H Boise 1,  Deepak Nagrath 2 3 4,  Mala Shanmugam 1
Affiliations

Affiliations

  • 1 Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA, USA.
  • 2 Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
  • 3 Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA.
  • 4 Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.
  • 5 Department of Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
  • 6 Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA.
PMID: 36170375 DOI: 10.1126/sciadv.abq5575
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.

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