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Ferrata Storti Foundation
Haematologica 2019 Volume 104(5):1016-1025
Chronic Lymphocytic Leukemia
Targeting intermediary metabolism enhances the efficacy of BH3 mimetic therapy
in hematologic malignancies
Aoula Al-Zebeeby,1 Meike Vogler,2 Mateus Milani,1 Caitlin Richards,1 Ahoud Alotibi,1 Georgia Greaves,1 Martin J.S. Dyer,3 Gerald M. Cohen1,4 and Shankar Varadarajan1,4*
1Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, UK; 2Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany; 3Ernest and Helen Scott Haematological Research Institute, Leicester Cancer Research Centre, University of Leicester, Leicester Royal Infirmary, UK and 4Department of Molecular and Clinical Cancer Pharmacology, Institute of Translational Medicine, University of Liverpool, 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 differ- ent 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 dif- ferent 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.
Introduction
Failure to undergo apoptosis is a cardinal feature of cancer and several targeted therapies, such as the small molecule inhibitors targeting specific members of the anti-apoptotic BCL-2 family - navitoclax/ABT-263 (targeting BCL-2, BCL-XL and BCL-w) and venetoclax/ABT-199 (BCL-2 specific) - are aimed at facilitating cancer cell clearance by enhanced apoptosis.1-4 Recently, selective inhibitors of BCL-XL (A- 1331852) and MCL-1 (A-1210477 and S63845) have also been synthesized.5-7 Despite their selectivity in targeting distinct anti-apoptotic BCL-2 family mem- bers, and remarkable potency in inducing rapid and extensive apoptosis in a wide variety of malignancies, resistance to BH3 mimetics, in particular venetoclax, is starting to be reported in the clinic. Elevated levels of multiple members of the anti-apoptotic BCL-2 family proteins, including BCL-XL and MCL-1, are often implicated in such chemoresistance.8-13 Although it may be possible to target these proteins with a combination of selective BH3 mimetics, the potential toxicities associated with such combination therapy may be problematic.
Altered metabolism is a promising approach to enhance the efficacy of chemotherapeutic agents, as a requirement for intermediary metabolites, such as glucose and glutamine, for the survival and proliferation of cancer cells is well doc-
Correspondence:
SHANKAR VARADARAJAN
svar@liverpool.ac.uk
Received: August 16, 2018. Accepted: November 20, 2018. Pre-published: November 22, 2018.
doi:10.3324/haematol.2018.204701
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/5/1016
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