Receptor tyrosine kinase inhibitors: Are they real tumor killers?

Inhibiting tumor growth by targeting the tumor vasculature was first proposed by Judah Folkman almost 40 years ago. Since then, different approaches and numerous drugs and agents have been developed to achieve this goal, either with the aim of inhibiting tumor neoangiogenesis or normalizing the tumor vasculature. Among the most promising therapeutic targets are receptor tyrosine kinases (RTKs), some of which are predominantly expressed on tumor endothelial cells, although they are sometimes also present on tumor cells. The majority of RTK inhibitors investigated over the past two decades competes with ATP at the active site of the kinase and therefore block the phosphorylation of intracellular targets. Some of these drugs have been approved for therapy, whereas others are still in clinical trials. Here, we discuss the scientific basis, current status, problems and future prospects of RTK inhibition in anti-tumor therapy. Neoangiogenesis is a complex process that occurs under physiological conditions and under various pathological conditions, such as wound healing, arthritis and cancer. In a seminal article published in 1971, Judah Folkman 1 postulated that it should be possible to stop tumor growth or even induce tumor regression by blocking the supply of oxygen and nutrients to cancer cells through disrupting vessel outgrowth. However, at that time, little was known about the role of tumor microenvironmental factors and the complex interplay of the numerous pathways that control neoangiogenesis. The biological basis of the regulation of angiogenesis was extensively studied in the following three decades. Early on, Folkman and Hanahan emphasized the concept of an angiogenic switch from an avascular to a vascular tumorgrowth phase. 2 The major environmental factor that promotes this angiogenic switch is hypoxia. In hypoxic cells, the hypoxia-inducible factor-1 (HIF-1) complex is stabilized and induces the expression of numerous genes, including the gene encoding vascular endothelial growth factor (VEGF). 3