Canagliflozin synergises with serine synthesis pathway inhibition mediating anti-leukaemic effects in T-cell acute lymphoblastic leukaemia

ABSTRACT: 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. Canagliflozin (cana) is an FDA-approved sodium glucose co-transporter 2 inhibitor with known off-target effects on complex I and glutamate dehydrogenase. To date, the effects of cana on T-ALL are not known. 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 anti-leukaemic effects. Collectively, our study reveals cana creates a metabolic vulnerability that can be further exploited via dietary manipulation to treat T-ALL

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Suspension Culture, Permanent Cell Line Cell, Jurkat Cell

DISEASE(S): Acute Leukemia

SUBMITTER: Fernando Manuel Garcia  

LAB HEAD: Nick Jones

PROVIDER: PXD069587 | Pride | 2025-10-27

REPOSITORIES: Pride