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Haematologica. 2019 May;104(5):1016-1025. doi: 10.3324/haematol.2018.204701. Epub 2018 Nov 22.

Targeting intermediary metabolism enhances the efficacy of BH3 mimetic therapy in hematologic malignancies.

Author information

1
Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, UK.
2
Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany.
3
Ernest and Helen Scott Haematological Research Institute, Leicester Cancer Research Centre, University of Leicester, Leicester Royal Infirmary, UK.
4
Department of Molecular and Clinical Cancer Pharmacology, Institute of Translational Medicine, University of Liverpool, UK.
5
Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, UK svar@liverpool.ac.uk.

Abstract

BH3 mimetics are novel targeted drugs with remarkable specificity, potency and enormous potential to improve cancer therapy. However, acquired resistance is an emerging problem. We report the rapid development of resistance in chronic lymphocytic leukemia cells isolated from patients exposed to increasing doses of navitoclax (ABT-263), a BH3 mimetic. To mimic such rapid development of chemoresistance, we developed simple resistance models to three different BH3 mimetics, targeting BCL-2 (ABT-199), BCL-XL (A-1331852) or MCL-1 (A-1210477), in relevant hematologic cancer cell lines. In these models, resistance could not be attributed to either consistent changes in expression levels of the anti-apoptotic proteins or interactions among different pro- and anti-apoptotic BCL-2 family members. Using genetic silencing, pharmacological inhibition and metabolic supplementation, we found that targeting glutamine uptake and its downstream signaling pathways, namely glutaminolysis, reductive carboxylation, lipogenesis, cholesterogenesis and mammalian target of rapamycin signaling resulted in marked sensitization of the chemoresistant cells to BH3 mimetic-mediated apoptosis. Furthermore, our findings highlight the possibility of repurposing widely used drugs, such as statins, to target intermediary metabolism and improve the efficacy of BH3 mimetic therapy.

PMID:
30467206
DOI:
10.3324/haematol.2018.204701
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