Understanding how kinase-targeted therapies work

Abstract

Kinases are central nodes in the cellular pathways that control differentiation, proliferation, apoptosis, motility, and invasion. Most if not all human tumors are thought to bear alterations in one or multiple kinase genes which therefore represent attractive therapeutic targets. Accordingly, intense drug discovery programs have led to the development of clinically effective kinase inhibitors. The road to generate a kinase inhibitor requires, in the initial phase, validation of the oncogenic potential of the corresponding kinase gene in cancer cells. As the catalytic domains of kinases are highly homologous, most inhibitors are predicted to affect multiple kinases. It is therefore important to ensure that a drug of interest acts by direct inhibition of its putative target. To address these issues, we devised a strategy to genetically inactivate the catalytic activity of a given kinase in human cells. This approach generates isogenic cells in which a certain kinase gene is expressed but is devoid of enzymatic activity thus mimicking the chronic pharmacological treatment of cancer cells with a specific and selective kinase inhibitor. This strategy is not limited to kinase genes but could be broadly applicable to any drug/protein combination in which the target enzymatic domain of a gene is known.