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

Menée à l'aide de lignées cellulaires de myélomes multiples, cette étude met en évidence un mécanisme par lequel l'inhibition de la chaîne de transport d'électrons, impliquée dans la phosphorylation oxydative mitochondriale, favorise la résistance des cellules cancéreuses aux inhibiteurs du protéasome

Résumé en anglais

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. Inhibition of the electron transport chain/OXPHOS promotes resistance to proteasome inhibitors in multiple myeloma.