Targeted Therapy With Imatinib: Hits and Misses?

Abstract

Targeted therapeutics are highly specific inhibitors of particular molecules and are, therefore, not broadly effective in diverse malignancies. Extensive preclinical and clinicalstudiesprovidebothclearexamplesoftheirefficacyand resounding examples of their shortcomings. Targeted therapies will require that we use them in a markedly different fashionthanweuseconventionaldrugsandwillbesuccessful only when they are used against biologically relevant targets in specific disease contexts. Imatinib mesylate (imatinib) is a success of targeted therapy. It is active against a number of related tyrosine kinases, namely ABL, BCR-ABL, KIT, PFGFR, and TEL. Imatinib has significant clinical efficacy in chronic myelogenous leukemia (CML) 1 and gastrointestinal stromal tumors (GISTs). 2 The reason that CML and GIST are effectively treated with imatinib is that they each contain a geneticchangeinvolvingthetargetedkinasesthatisintegral to the biology of the malignancy. CML contains a translocation between the breakpoint cluster region and the ABL genethatleadstoaconstitutivelyactivekinase.GISTscommonly express mutated KIT that is constitutively activated; some contain a wild-type KIT and/or a mutated plateletderivedgrowthfactorreceptoralpha(PDGFRA).Theactivityofthesekinasesprovidesthemalignantcellswithgrowth and survival signals. However, it is this activity that is so very effectively turned off by imatinib. The significant responses in patients with CML and GIST earned the agent rapidapprovalbytheUnitedStatesFoodandDrugAdministration,aswellassignificantnotorietyinboththemedical and lay press. Many have sought to use the drug in hopes of having similar dramatic responses in other cancers.