Targeting glutamine metabolism in multiple myeloma enhances BIM binding to BCL-2 eliciting synthetic lethality to venetoclax

Abstract

Multiple myeloma (MM) is a plasma cell malignancy that is largely incurable due to development of resistance to therapy-elicited cell death. Nutrients are intricately connected to maintenance of cellular viability in part by inhibition of apoptosis. We were interested to determine if examination of metabolic regulation of BCL-2 proteins may provide insight on alternative routes to engage apoptosis. MM cells are reliant on glucose and glutamine and withdrawal of either nutrient is associated with varying levels of apoptosis. We and others have demonstrated that glucose maintains levels of key resistance-promoting BCL-2 family member, myeloid cell leukemic factor 1 (MCL-1). Cells continuing to survive in the absence of glucose or glutamine were found to maintain expression of MCL-1 but importantly induce pro-apoptotic BIM expression. One potential mechanism for continued survival despite induction of BIM could be due to binding and sequestration of BIM to alternate pro-survival BCL-2 members. Our investigation revealed that cells surviving glutamine withdrawal in particular, enhance expression and binding of BIM to BCL-2, consequently sensitizing these cells to the BH3 mimetic venetoclax. Glutamine deprivation-driven sensitization to venetoclax can be reversed by metabolic supplementation with TCA cycle intermediate α-ketoglutarate. Inhibition of glucose metabolism with the GLUT4 inhibitor ritonavir elicits variable cytotoxicity in MM that is marginally enhanced with venetoclax treatment, however, targeting glutamine metabolism with 6-diazo-5-oxo-l-norleucine uniformly sensitized MM cell lines and relapse/refractory patient samples to venetoclax. Our studies reveal a potent therapeutic strategy of metabolically driven synthetic lethality involving targeting glutamine metabolism for sensitization to venetoclax in MM.

Dependence on glutamine uptake and glutamine addiction characterize myeloma cells: a new attractive target

“…56 Others recently showed that CB-839 blocks MM growth and synergized with pomalidomide in a preclinical model, 57 and a phase 1 trial with CB-839 in patients with R-MM is currently under investigation. 58 Moreover, it has been recently reported that Gln withdrawal enhanced MM cell sensitivity to BH3 mimetics venetoclax (ABT-199), a new antimyeloma drug currently under investigation, 59 and that ritonavir increases the Gln reliance of MM cells. 60 Overall, these data and our results suggest that Gln addiction and uptake could be a potential new therapeutic strategy in MM patients.…”

The potential of inhibiting glutamine uptake as a therapeutic target for multiple myeloma

“…First, the efficacy of such an approach requires a strict dependence of MM cells on extracellular Gln. However, MM cells relatively resistant to Gln depletion have been recently reported [7]. Given that GS expression was not assessed in that study, the possibility exists that sensitivity to Gln depletion associates with absent-to-low GS expression.…”

“…Interestingly, in MM cells, Gln shortage elicits synthetic lethality to venetoclax, a BH3-mimetic drug [7]. Although the elegant molecular mechanism described in that study may not be specific for MM cells, several contributions have reported that Gln shortage synergizes chemotherapeutic agents in a variety of cancers.…”

“…However, two recent, separate studies have reported GS-positive MM cells [16] and MM cells relatively resistant to Gln depletion [7]. A correlation between GS expression and lack of Gln dependence is therefore likely, although not demonstrated yet.…”

Rational combination strategies to enhance venetoclax activity and overcome resistance in hematologic malignancies

“…Bajpai et al reported that interventions that depleted cellular glutamine resulted in diminished binding of Bim to Mcl-1 in multiple myeloma cells, and a significant increase in sensitivity to venetoclax [65]. Specifically, they found that the glutamine antagonist DON sharply increased venetoclax lethality in cultured and primary multiple myeloma cells, including those obtained from patients resistant to standard therapy.…”