ABSTRACT

The development of targeted therapies to disrupt cancer cell signaling is a burgeoning area of experimental therapeutics for both solid tumors and hematologic malignancies. Cell signaling pathways are tightly regulated by the transfer of phosphate from adenosine triphosphate (ATP) to tyrosine residues on substrate proteins in reactions catalyzed by tyrosine kinase (TK) enzymes. Abnormal activation of such TKs by gene mutation or aberrant expression, with the resultant dysregulation of intracellular pathways, has been implicated in oncogenesis. The original drug paradigm that employs the targeted inhibition of an abnormal TK (Bcr-Abl) is that of imatinib mesylate (STI571) in chronic myelogenous leukemia (CML). The development of other TK inhibitors for use in acute leukemias, such as those targeting the overexpression of c-KIT and mutant FLT-3, are discussed in detail in previous chapters.