| RRC ID |
86949
|
| 著者 |
Nirachonkul W, Farrell MP, Tolbert TJ, Okonogi S, Tima S, Anuchapreeda S, Chiampanichayakul S, Siahaan TJ.
|
| タイトル |
Mislocalisation of FLT3-ITD receptor contributes to MV4-11 leukaemia cell resistance to antibody-drug conjugate.
|
| ジャーナル |
J Enzyme Inhib Med Chem
|
| 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. These findings highlight that effective lysosomal targeting is essential for ADC activity and suggest that optimising linker design or restoring lysosome trafficking may enhance FLT3-targeted ADC in AML.
|
| 巻・号 |
41(1)
|
| ページ |
2638027
|
| 公開日 |
2026-12-1
|
| DOI |
10.1080/14756366.2026.2638027
|
| PMID |
41784256
|
| PMC |
PMC12964472
|
| MeSH |
Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm* / drug effects
Drug Screening Assays, Antitumor
Humans
Immunoconjugates* / chemistry
Immunoconjugates* / pharmacology
Leukemia, Myeloid, Acute* / drug therapy
Leukemia, Myeloid, Acute* / metabolism
Leukemia, Myeloid, Acute* / pathology
Molecular Structure
Protein Kinase Inhibitors* / chemical synthesis
Protein Kinase Inhibitors* / chemistry
Protein Kinase Inhibitors* / pharmacology
Structure-Activity Relationship
Tumor Cells, Cultured
fms-Like Tyrosine Kinase 3* / antagonists & inhibitors
fms-Like Tyrosine Kinase 3* / genetics
fms-Like Tyrosine Kinase 3* / metabolism
|
| IF |
4.673
|
| リソース情報 |
| ヒト・動物細胞 |
EoL-1 cell(RCB0641) |
