Mislocalisation of FLT3-ITD receptor contributes to MV4-11 leukaemia cell resistance to antibody-drug conjugate
Wariya Nirachonkul, Mark P. Farrell, Thomas J. Tolbert, Siriporn Okonogi, Singkome Tima, Songyot Anuchapreeda, Sawitree Chiampanichayakul, Teruna J. Siahaan
TL;DR
The study shows that FLT3-ITD leukaemia cells resist antibody-drug conjugates due to mislocalization of the receptor, which affects drug delivery.
Contribution
The novel contribution is identifying how FLT3 trafficking differences impact ADC efficacy in leukaemia cells.
Findings
FLT3 mAb traffics to lysosomes in FLT3-wt cells but accumulates in the Golgi in FLT3-ITD cells.
Anti-FLT3 mAb-MMAE showed lower cytotoxicity in MV4-11 cells due to impaired lysosomal trafficking.
Effective lysosomal targeting is essential for ADC activity in FLT3-targeted therapies.
Abstract
FMS-like tyrosine kinase 3 (FLT3/CD135) regulates haematopoiesis and is frequently mutated as FLT3-internal tandem duplication (FLT3-ITD) in acute myeloid leukaemia (AML), associated with poor prognosis. Although FLT3 inhibitors show clinical benefits, resistance remains a challenge. This study hypothesises that antibody-drug conjugate (ADC) efficacy depends on distinct FLT3 trafficking mechanisms in FLT3-wt and FLT3-ITD cells. Confocal imaging showed that in THP-1 (FLT3-wt) cells, FLT3 mAb trafficked to lysosomes, while in MV4-11 (FLT3-ITD) cells, it accumulated in the Golgi. To evaluate the impact of this trafficking difference, we synthesised an anti-FLT3 mAb-MMAE, linked via a Val-Cit-PAB linker at the Fc N-glycan, which exhibited lower cytotoxicity in MV4-11 than THP-1 cells, indicating that the impaired lysosomal trafficking of FLT3-ITD limits drug release and reduces ADC potency.…
Genes, proteins, chemicals, diseases, species, mutations and cell lines named across the full text — each resolved to its canonical identifier and authoritative record.
Click any figure to enlarge with its caption.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10Peer Reviews
No public reviews on file for this paper yet. If you reviewed it on a platform where reviews are public (OpenReview, ICLR, NeurIPS, ICML), you can paste yours below so the community can read it here.
Videos
No videos yet. Explain this paper in a talk, walkthrough, or lecture? Add one.
Taxonomy
TopicsAcute Myeloid Leukemia Research · Chronic Lymphocytic Leukemia Research · Chronic Myeloid Leukemia Treatments