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

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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.

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Acknowledgements

This research was supported by the American Cancer Society Research scholar grant (RSG-11-254-01-CSM) to MS. LHB is a Georgia Research Alliance distinguished cancer scientist and also received support from the TJ Martell Foundation and P30CA138292.

Author contributions

RB and MS conceived the research with conceptual advice from LHB; RB, SMM, CW and MS performed experimentation and data analysis with advice from LHB. HEVH, AKN and SL oversaw collection of myeloma patient samples and provided conceptual advice. RB and MS wrote the manuscript and MS supervised the project.

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Correspondence to M Shanmugam.

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Competing interests

LHB is a consultant for Onyx Pharmaceuticals and Novartis; AKN is consultant for Onyx Pharmaceuticals and Spectrum pharmaceuticals; SL is a consultant for Millennium, Onyx Pharmaceuticals, Novartis, BMS, Janssen and Celgene. The remaining authors declare no conflict of interest.

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Bajpai, R., Matulis, S., Wei, C. et al. Targeting glutamine metabolism in multiple myeloma enhances BIM binding to BCL-2 eliciting synthetic lethality to venetoclax. Oncogene 35, 3955–3964 (2016) doi:10.1038/onc.2015.464

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