Despite the findings of the RATIFY study and the FDA approval of midostaurin, the survival of Acute Myeloid Leukemia (AML) patients harboring Fms-like tyrosine kinase 3 (FLT3) internal tandem duplication (FLT3-ITD) mutations remains inferior due to possible underlying resistance mechanisms to targeted inhibitors that may decrease the effectiveness of these new approaches.1,2
On 20th February 2018, in Blood, Paolo Gallipoli from University of Cambridge, Cambridge, UK, and colleagues published results from their study, which aimed to identify novel cellular adaptive resistance mechanisms to FLT3-ITD tyrosine kinase (TK) inhibitor (TKI) treatment in FLT3-ITD mutated AML.
To do this, the authors performed an unbiased genome-wide CRISPR/Cas9 synthetic lethality screen on FLT3-ITD AML cell lines treated with a highly potent and specific FLT3-TKI (AC220 [quizartinib]). Gene analysis revealed that genes involved in metabolic pathways were highly regulated in FLT3-ITD AML cells after treatment with AC220. In particular, glutaminase (GLS), a mitochondrial enzyme that catalyses the conversion of glutamine to glutamate, was synthetically lethal with FLT3-TKI treatment. Gallipoli et al. further investigated the clinical role of GLS in FLT3-ITD AML cells treated with AC220.
- Treatment with AC220 significantly impaired glycolysis and glucose utilization in FLT3-ITD cells but glutamine metabolism was not affected
- Treatment with AC220 increased the mitochondrial membrane potential and mitochondrial mass in FLT3-ITD cells
- Glutamine metabolism significantly impacted the tricarboxylic acid (TCA) cycle and redox metabolism in AC220- treated cells
- Treatment of FLT3-ITD cells with AC220 and CB839 (a potent and selective GLS inhibitor) resulted in reduced oxygen consumption, increased redox metabolism, and increased apoptosis
In summary, these data confirm that glutamine metabolism is important in supporting the TCA cycle and redox metabolism in FLT3-ITD cells treated with AC220 in vitro. Using primary samples obtained from patients with FLT3-ITD AML, the authors found that AC220 treatment led to a reduction in glycolytic capacity. Additionally, combined treatment with AC220 and CB839 led to decreased basal oxygen consumption in primary AML samples. These data confirm that “combined targeting of FLT3 TK activity and glutamine metabolism decreases FLT3-ITD mutant cells leukemogenic potential in vitro and in vivo.”
The authors concluded by stating that their data highlights the “the role of metabolic adaptations as a resistance mechanism to several TKI, and suggests glutaminolysis as a therapeutically targetable vulnerability when combined with specific TKI in FLT3-ITD and other TK activating mutation driven leukemias.”