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A new monoclonal antibody that blocks dimerisation and inhibits c-kit mutation-driven tumour growth
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A new monoclonal antibody that blocks dimerisation and inhibits c-kit mutation-driven tumour growth
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A new monoclonal antibody that blocks dimerisation and inhibits c-kit mutation-driven tumour growth
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Journal Article
A new monoclonal antibody that blocks dimerisation and inhibits c-kit mutation-driven tumour growth
2021
Overview
Purpose
Imatinib, a small-molecule tyrosine kinase inhibitor, has shown good clinical activity by inhibiting adenosine triphosphate (ATP) binding to the receptor. Unfortunately, majority of patients eventually develop drug resistance, which limits the long-term benefits of the tyrosine kinase inhibitors and poses a significant challenge in the clinical management of GIST. The aim of our study was to explore the feasibility of blocking KIT dimerisation upstream of the phosphorylation in imatinib-resistant GIST.
Method
KITMAb was prepared using hybridoma technique. The biological function of KITMAb was examined in KIT-dimer-expressing cells constructed by transfecting with liposomes using enzyme linked immunosorbent assay (ELISA), immunohistochemistry, western blot, MTT, Annexin V/FITC, and flow cytometry assay, respectively.
Results
KIT-dimer was expressed in 293 cells transfected with
c-kit
mutated-type pcDNA3.1. Treatment of KIT-dimer-expressing cells with the KITMAb significantly decreased the expression of both KIT-dimer and other phosphorylated proteins of KIT downstream signalling pathway. Furthermore, KITMAb slowed down cell growth and reduced the proportion of cells in the proliferative phase (S + G2-M). Finally, we also found that KITMAb treatment accelerated cell apoptosis. These results indicate that KITMAb strongly inhibits KIT receptor dimerisation-mediated signalling pathway and cell growth responses in vitro
.
Conclusions
We demonstrate
c-kit
mutation-driven KIT auto-dimerisation prior to tyrosine kinase phosphorylation as same as the procedure in ligand-dependent signalling pathway and describe a monoclonal antibody, KITMAb, with strong affinity to the dimerisation domain of KIT that blocks the important step in both the KIT signalling pathways. Further, the results suggest that treatment with KITMAb may be potentially therapeutic in imatinib-resistant GIST.
Publisher
Springer Berlin Heidelberg,Springer Nature B.V
Subject
/ Antibodies, Monoclonal - pharmacology
/ Biomarkers, Tumor - genetics
/ Biomarkers, Tumor - metabolism
/ Enzyme-linked immunosorbent assay
/ Gene Expression Regulation, Neoplastic
/ Humans
/ Imatinib
/ Medicine
/ Mutation
/ Oncology
/ Original Article – Cancer Research
/ Proto-Oncogene Proteins c-kit - chemistry
/ Proto-Oncogene Proteins c-kit - genetics
/ Proto-Oncogene Proteins c-kit - immunology
/ Proto-Oncogene Proteins c-kit - metabolism
/ Tumors
