Canagliflozin synergises with serine restriction mediating anti-leukaemic effects in T-cell acute lymphoblastic leukaemia
T-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy commonly driven by NOTCH1 activating mutations. A concomitant feature associated with NOTCH1 mutations is heightened oxidative metabolism enabling the exponential proliferation of T-ALL blasts. As such, targeting mitochondrial metabolism in T-ALL is an attractive therapeutic avenue. Related to this, canagliflozin (cana), is an FDA-approved sodium glucose co-transporter 2 inhibitor with known off-target effects on complex I and glutamate dehydrogenase, but its potential anti-leukaemic effects remain unexplored. Here, we show that cana possesses potent anti-leukaemic effects underpinned by proliferative defects, cell cycle disruption and apoptosis. These anti-leukaemic effects driven by cana, are attributed to a perturbed tricarboxylic acid (TCA) cycle and mitochondrial metabolism, and elevated mitochondrial ROS. Proteomic analysis revealed that cana treatment resulted in a compensatory increase in the expression of ATF4 targets, including upregulation of serine biosynthesis pathway and one-carbon metabolism enzymes. As such, restriction of serine and glycine synergized with cana treatment, further enhancing its anti-leukaemic effects. Collectively, our study reveals a cana-driven metabolic vulnerability that can be further exploited via dietary manipulation to treat T-ALL.
Authors
- Le Le (ORCID: https://orcid.org/0000-0002-1013-2328)
- Nitesh Sharma (ORCID: https://orcid.org/0000-0002-6228-0488)
- Fernando M. Ponce-Garcia (ORCID: https://orcid.org/0000-0003-0651-2704)
- J. Cronin (ORCID: https://orcid.org/0000-0002-0590-9462)
- H. Eric (ORCID: https://orcid.org/0000-0001-8556-980X)
- Catherine Moore (ORCID: https://orcid.org/0000-0001-8934-0930)
- Russell G. Jones (ORCID: https://orcid.org/0000-0003-2250-4675)
- Ksenia Matlawska‐Wasowska (ORCID: https://orcid.org/0000-0002-9903-5793)
- Julianna Blagih (ORCID: https://orcid.org/0000-0002-5010-2879)
- Silpita Paul (ORCID: https://orcid.org/0000-0003-1682-3151)
- Nicholas Jones (ORCID: https://orcid.org/0000-0003-4846-5117)
- Paraskevi Diamanti
- Christina Halsey (ORCID: https://orcid.org/0000-0001-5449-5246)
- Allison Blair (ORCID: https://orcid.org/0000-0002-9759-5156)
- Marc Hennequart (ORCID: https://orcid.org/0000-0003-4360-6830)
- Yasmin R Jenkins
- Marc R. Mansour (ORCID: https://orcid.org/0000-0001-6835-3791)
- Daniel Herranz (ORCID: https://orcid.org/0000-0003-1768-5969)
- B. Jenkins (ORCID: https://orcid.org/0000-0001-8378-8929)
- Emma E. Vincent (ORCID: https://orcid.org/0000-0002-8917-7384)
- Victoria D Assmann (ORCID: https://orcid.org/0009-0000-3139-1567)
- Sophie Rouvray
Institutions
- Rutgers, The State University of New Jersey (US)
- NHS Blood and Transplant (GB)
- Van Andel Institute (US)
- University of Namur (BE)
- The Francis Crick Institute (GB)
- Johnson University (US)
- Hôpital Maisonneuve-Rosemont (CA)
- University of Alabama at Birmingham (US)
- University of Bristol (GB)
- Swansea University (GB)
- University College London (GB)
- University of Glasgow (GB)
Publication Details
- Journal
- Molecular Metabolism
- Published
- 2025-10-19
- DOI
- https://doi.org/10.1016/j.molmet.2025.102275
- Citations
- 1
- Primary Topic
- Diabetes Treatment and Management
- Type
- article
- Field-Weighted Citation Impact
- 1.29