C-KIT receptor on mast cells as a possible target for the treatment of colorectal cancer

Abstract

The role of mast cells (MCs) in the development and progression of colorectal cancer has long been investigated. A high density of these immune cells, which are able to release numerous pro-tumorigenic factors, has been associated with poor prognosis. One of the most important receptors present on mast cells is the c-KIT receptor, whose activation is dependent on stem cell factor (SCF) ligand, a major cytokine that influences mast cells number. This has led to the development of drugs able to inhibit this receptor and thus decrease mast cell density (MCD). One of the main classes of drugs are the tyrosine kinase inhibitors (TKIs) that were first developed in 2001. Despite their important role and efficacy, TKIs used so far for treatment in colorectal cancer are multi-target inhibitors which present some limitations. For instance, the development of resistance and high toxicity due to off-target effects are common. Future studies should, therefore, lead to a resolution of these two major limitations by increasing affinity for the target. One possible solution, presented in this report, could be the development of new drugs belonging to the third generation tyrosine kinase inhibitors characterized by a single target and irreversible receptor binding.