Complex I inhibition sensitises FLT3-ITD AML models to gilteritinib

Researchers used a metabolism-focused CRISPR-Cas9 screen and transcriptomic profiling of gilteritinib-resistant cells and primary samples to investigate treatment tolerance in FLT3-ITD AML. They identified NDUFS2, a core subunit of mitochondrial complex I, as upregulated in acquired resistance and preferentially expressed in FLT3-ITD AML. The article does not report sample sizes in the supplied text.

NDUFS2 knockdown impaired complex I activity, oxidative phosphorylation, mitochondrial membrane potential and ATP production, while promoting apoptosis and sensitising AML cells to gilteritinib. The complex I inhibitor IACS-010759 also enhanced gilteritinib activity in cell lines and primary FLT3-ITD samples. In a patient-derived xenograft model, the combination reduced leukaemia burden; genetic NDUFS2 knockdown prolonged survival in a separate xenograft model. Short-term dosing produced no overt toxicity in a preliminary murine assessment.

These findings support further preclinical investigation of NDUFS2-dependent metabolism as a potential resistance mechanism. They do not establish a treatment strategy for patients: efficacy and safety have not been demonstrated in clinical studies, and the reported animal safety assessment was limited to the tested short-term schedule.