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

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journal contribution
posted on 08.04.2019, 12:04 by A Al-Zebeeby, M Vogler, M Milani, C Richards, A Alotibi, G Greaves, MJS Dyer, GM Cohen, S Varadarajan
BH3 mimetics are novel targeted drugs with remarkable specificity and 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 have 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 haematological cancer cell lines. In these models, resistance could be attributed neither to consistent changes in expression levels of the anti-apoptotic proteins nor interactions among different pro- and anti-apoptotic BCL-2 family members. Using genetic silencing, pharmacological inhibition and metabolic supplementation, we report that targeting of glutamine uptake and its downstream signalling pathways, namely glutaminolysis, reductive carboxylation, lipogenesis, cholesterogenesis and mTOR signalling result in marked sensitisation 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.

Funding

We thank AbbVie for inhibitors and Prof. J. Borst for antibodies. This work was supported by a NorthWest Cancer Research Grant CR1040 (Varadarajan and Cohen), a studentship from the Ministry of Higher Education and Scientific Research and the University of Al-Qadisiyah, Iraq (Al-Zebeeby), a Science Without Borders studentship, CNPq 233624/2014-7, from the Ministry of Education, Brazil (Milani) and a studentship from the Prince Sattam Bin Abdulaziz University, Saudi Arabia (Alotibi).

History

Citation

Haematologica, 2018

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Cancer Research Centre

Version

AM (Accepted Manuscript)

Published in

Haematologica

Publisher

Ferrata Storti Foundation with European Hematology Association

eissn

1592-8721

Acceptance date

20/11/2018

Copyright date

2018

Available date

08/04/2019

Publisher version

http://www.haematologica.org/content/early/2018/11/19/haematol.2018.204701

Language

en