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A. Al-Zebeeby et al.
inhibitor, only recently having received approval for treat- ment of refractory CLL.4 The development of BH3 mimetics to target BCL-XL and MCL-1 in patients will be extremely valuable in the treatment of several types of cancer. However potential mechanisms of resistance to BH3 mimetics need to be recognized as they emerge and ways to circumvent resistance identified. Several resist- ance mechanisms, including mutations of the target site,29 post-translational modifications,30,31 and elevated levels of anti-apoptotic BCL-2 family members,8,11,32,33 have already been identified. While some of these resistance mecha- nisms could be overcome by co-administration of other specific BH3 mimetics that target BCL-XL and/or MCL-1,5- 7 such inhibitors are not yet clinically available and the potential toxicities associated with the simultaneous inhi- bition of multiple BCL-2 family members are not known.
Attempts to identify measures that could overcome chemoresistance have led to exploration of the therapeu- tic potential of modulating intermediary metabolism in BH3 mimetic-mediated apoptosis.19,20,34 Although the mechanisms by which glutamine could regulate cancer cell proliferation have been extensively studied, the interrelationship between glutamine metabolism and apoptosis requires further study. It has been previously reported that glutamine-mediated apoptosis is depend- ent on Myc14 and that c-Myc activates glutaminolysis by upregulating both the glutamine transporter, SLC1A5, and glutaminase, GLS-1.35,36 However, we were unable to detect an increase in expression levels of Myc, SLC1A5 or GLS-1 in our resistance models (Figure 3 and data not shown). The ability of glutamine to regulate apoptosis and/or chemoresistance could also be due to its regulato- ry effect on mitochondrial oxidative phosphorylation.20
Although we do not entirely understand how glutamine metabolism impinges on apoptosis at this point, our data strongly support the notion that modulating glutamine metabolism and its related signaling pathways, such as reductive carboxylation, lipogenesis, cholesterogenesis and mTOR signaling, could enhance BH3 mimetic-medi- ated apoptosis in several hematologic malignancies (Figures 3-6). This is particularly promising, as glutami- nase inhibitors, such as CB-839 and related drugs are already in clinical trials for the treatment of several malignancies20,37 and other drugs targeting cholesterogen- esis, such as statins are the most commonly prescribed drugs to millions of people worldwide. While this man- uscript was in preparation, an independent study com- paring a large cohort of CLL patients, many of whom were statin users, found that response to venetoclax/ ABT-199 was enhanced among statin users in three dif- ferent clinical trials.44 These findings highlight the possi- bility of repurposing several drugs targeting the interme- diary metabolic pathways in conjunction with BH3 mimetic therapy to enhance therapeutic effectiveness and overcome the emerging chemoresistance in several cancers.
Acknowledgments
We thank AbbVie for inhibitors and Prof. J. Borst for antibod- ies. This work was supported by a NorthWest Cancer Research grant CR1040 (to SV and GMC), a studentship from the Ministry of Higher Education and Scientific Research and the University of Al-Qadisiyah, Iraq (fpr AA-Z), a Science Without Borders studentship, CNPq 233624/2014-7, from the Ministry of Education, Brazil (for MM) and a studentship from the Prince Sattam Bin Abdulaziz University, Saudi Arabia (for AA).
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