Evidence map›Paper›PMID 41784256›Full record

ArticleJournal of enzyme inhibition and medicinal chemistry2026

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

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In one paragraph

Article in Journal of enzyme inhibition and medicinal chemistry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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3 · Its place in the literature

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4 · The record

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5 · Who and what money

Authors and funding

8 authors.

Wariya NirachonkulDepartment of Medical Technology, Chiang Mai University, Chiang Mai, Thailand.
Mark P FarrellDepartment of Medicinal Chemistry, The University of Kansas, Lawrence, KS, USA.
Thomas J TolbertDepartment of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS, USA.
Siriporn OkonogiDepartment of Pharmaceutical Sciences, Chiang Mai University, Chiang Mai, Thailand.
Singkome TimaDepartment of Medical Technology, Chiang Mai University, Chiang Mai, Thailand.
Songyot AnuchapreedaDepartment of Medical Technology, Chiang Mai University, Chiang Mai, Thailand.
Sawitree ChiampanichayakulDepartment of Medical Technology, Chiang Mai University, Chiang Mai, Thailand.
Teruna J SiahaanDepartment of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS, USA.

Funding

Reshaping ApoE4 and Alzheimer's Brains with ApoE2R01AG071682 · NIA · UNIVERSITY OF KANSAS LAWRENCE · PI TERUNA J. SIAHAAN, Liqin Zhao · 2022 to 2026
$3.4M
A Novel Method to Enhance Drug Delivery to the BrainR01AG082273 · NIA · UNIVERSITY OF KANSAS LAWRENCE · PI KRZYSZTOF KUCZERA, TERUNA J. SIAHAAN · 2024 to 2026
$1.4M
NIA NIH HHS R01 AG071682NIA NIH HHS R01 AG082273
6 · The paper itself

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.

Indexed as

Antibodies, MonoclonalAntineoplastic AgentsDrug Resistance, Neoplasmfms-Like Tyrosine Kinase 3ImmunoconjugatesLeukemia, Myeloid, AcuteProtein Kinase InhibitorsCell ProliferationDose-Response Relationship, DrugDrug Screening Assays, AntitumorHumansMolecular StructureStructure-Activity RelationshipTumor Cells, CulturedAntibodies, MonoclonalAntineoplastic AgentsFLT3 protein, humanfms-Like Tyrosine Kinase 3ImmunoconjugatesProtein Kinase Inhibitorsacute myeloblastic leukaemia (AML)antibody-drug conjugates (ADCs)FLT3-internal tandem duplication (FLT3-ITD)FLT3-MMAE conjugateMV4-11

Identifiers

PMID41784256
PMCPMC12964472

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.