Glutaminase inhibitor CB-839 synergizes with carfilzomib in resistant multiple myeloma cells

Abstract

Curative responses in the treatment of multiple myeloma (MM) are limited by the emergence of therapeutic resistance. To address this problem, we set out to identify druggable mechanisms that convey resistance to proteasome inhibitors (PIs; e.g., bortezomib), which are cornerstone agents in the treatment of MM. In isogenic pairs of PI sensitive and resistant cells, we observed stark differences in cellular bioenergetics between the divergent phenotypes. PI resistant cells exhibited increased mitochondrial respiration driven by glutamine as the principle fuel source. To target glutamine-induced respiration in PI resistant cells, we utilized the glutaminase-1 inhibitor, CB-839. CB-839 inhibited mitochondrial respiration and was more cytotoxic in PI resistant cells as a single agent. Furthermore, we found that CB-839 synergistically enhanced the activity of multiple PIs with the most dramatic synergy being observed with carfilzomib (Crflz), which was confirmed in a panel of genetically diverse PI sensitive and resistant MM cells. Mechanistically, CB-839 enhanced Crflz-induced ER stress and apoptosis, characterized by a robust induction of ATF4 and CHOP and the activation of caspases. Our findings suggest that the acquisition of PI resistance involves adaptations in cellular bioenergetics, supporting the combination of CB-839 with Crflz for the treatment of refractory MM.

miR-22 suppresses DNA ligase III addiction in multiple myeloma

“…Interestingly, we found that upregulation of LIG3 is associated to bortezomib resistance and that LIG3 downregulation is highly toxic and partially restore drug sensitivity in bortezomib-resistant cells. These findings could be consistent with recent evidence which showed that bortezomib resistance in malignant plasmacells is associated to high dependency on increased mitochondrial activity and that mitochondrial activity modulation decreases bortezomib resistance [57][58][59].…”

A metabolic switch in proteasome inhibitor-resistant multiple myeloma ensures higher mitochondrial metabolism, protein folding and sphingomyelin synthesis

“…The data highlight increased antioxidant capacity, higher redox homeostasis and NAD + levels as the key metabolic changes in PI-resistance and are consistent with findings from earlier models including our own proteomic data. [5][6][7][8][9][10][11][12][13] We functionally validated the increased capacity of PIresistant cells to buffer the formation of reactive oxygen species (ROS), demonstrating 2-to 4-fold lower ROS levels in these cells than in PI-sensitive cells, confirming a significantly higher antioxidant capacity (Figure 2A). Consistent with this, PI-resistant cells are more resistant than PI-sensitive cells to H2O2-induced cytotoxicity (Online Supplementary Figure S4, Online Supplementary Table S2).…”

CHCHD4 regulates tumour proliferation and EMT-related phenotypes, through respiratory chain-mediated metabolism

“…From a therapeutic perspective, mitochondrial metabolism is an attractive target for treatment regimes, but is not without significant risk of toxicity. Agents which target the mitochondria are potently anti-proliferative, and several small molecules are in clinical trials which inhibit mitochondrial metabolic pathways [14,15,23]. The present study points to a potential complication with this kind of therapeutic strategy however; in that targeting mitochondrial metabolism (e.g.…”

“…fluorouracil) have been used clinically for decades [13]. Therapies which target amino acid synthesis are emerging in clinical development, and are showing promise [14][15][16].…”