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.
Highlights
Multiple Myeloma (MM) is the second most common hematological malignancy, accounting for approximately 25,000 new cases and 12,000 deaths per year in the United States, with a 5-year median survival rate of 50% [1]
BzR cells were negative for PSMB5 gene mutations that have been reported by others in proteasome inhibitors (PIs) resistant cell models (Supplementary Figure 2), [4, 29] suggesting that resistance is the result of cellular adaptations that allow cells to evade the cytotoxic effects of PIs rather than mutational events that interfere with PI binding and inhibition of the proteasome
We found that PI resistant cells had a significantly higher basal oxygen consumption rate (OCR) and mitochondrial respiratory capacity (Figure 1A–1B, Supplementary Figure 3A) compared to sensitive parental cells
Summary
Multiple Myeloma (MM) is the second most common hematological malignancy, accounting for approximately 25,000 new cases and 12,000 deaths per year in the United States, with a 5-year median survival rate of 50% [1]. They elicit their anti-MM effects through binding to the PSMb5 subunit of the 26S proteasome and inhibiting the chymotrypsin-like protease activity of the complex This results in the disruption of normal protein homeostasis and the concomitant induction of cellular proteotoxic stress, proving to be a effective strategy against MM plasma cells, which are naturally designed to mass-produce large multimeric immunoglobulin proteins. PSMB5 mutations have been shown to reduce binding of bortezomib (Btz) and carfilzomib (Crflz) to the proteasome in MM and non-MM cell models of PI resistance [2,3,4,5,6], alterations in redox homeostasis have been implicated in protecting MM cells from PI-induced oxidative damage and cell death [6,7,8], and adaptations involving the cellular protein folding machinery and energy regulation have been implicated in the PI resistance phenotype [6, 9]
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