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

• Authors: Vikas Gupta, Emory University; Aditi Sharma, Emory University; Remya Nair, Emory University; Abhinav Achreja, University of Michigan, Ann Arbor; Anjali Mittal, University of Michigan, Ann Arbor; Pulkit Gupta, Emory University; Kamakshi Balakrishnan, Emory University; Claudia L Edgar, Emory University; Olamide Animasahun, University of Michigan, Ann Arbor; Bhakti Dwivedi, Emory University; Benjamin Barwick, Emory University; Shannon Matulis, Emory University; Manoj Bhasin, Emory University; Sagar Lonial, Emory University; Ajay Nooka, Emory University; Arun P Wiita, University of California, San Francisco; Lawrence Boise, Emory University; Deepak Nagrath, University of Michigan, Ann Arbor; Malathy Shanmugam, Emory University
• Journal Title: Science Advances
• Volume: Volume 8, Number 39
• Publisher: American Association for the Advancement of Science | 2022-09-30, Pages eabq5575-eabq5575
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1126/sciadv.abq5575
• Subjects: Engineering, Biomedical; Biology, Biostatistics
• Keywords: Antiporters; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cystine; Glutamates; Humans; Multiple Myeloma; Proteasome Inhibitors; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

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.