A New Monoclonal Antibody that Blocks KIT Dimerisation and Inhibits Gastrointestinal Stromal Tumour Growth

Gastrointestinal stromal tumour (GIST) is the most common sarcoma of the gastrointestinal tract, and arises owing to oncogenic mutations in c-kit that result in constitutive auto-phosphorylation of KIT in the absence of ligand binding. Small-molecule tyrosine kinase inhibitors have shown good clinical activity by inhibiting 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. Here, 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. Treatment of KIT-dimer-expressing cells with the KITMAb slowed down cell growth. Furthermore, KITMAb reduced the proportion of cells in the proliferative phase (S+G2-M). Finally, we also demonstrate 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. Further, the results suggest that treatment with KITMAb may be potentially therapeutic in imatinib-resistant GIST.