Multiple TKIs approved in recent months

Abstract

Evolution of TKIs Patients with CML and ALL Imatinib (Gleevec—Novartis) was approved more than a decade ago as a targeted leukemia therapy (i.e., Bcr-Abl TKI). Since that time, researchers have uncovered much information regarding its resistance mechanisms and potential ways to overcome resistance. Imatinib resistance reportedly occurs in approximately 33% of patients and can be subclassifi ed as Bcr-Abl–dependent or Bcr-Abl–independent. The BcrAbl–dependent mechanisms involve Bcr-Abl mutation and amplifi cation, resulting in an alteration of imatinib’s binding affi nity to the Bcr-Abl tyrosine kinase. One of the most frequently identifi ed mutations is T315l. Second-generation TKIs such as dasatinib (Sprycel—Bristol-Myers Squibb) and nilotinib (Tasigna—Novartis) are more potent than imatinib and can be used as fi rst-line agents for the management of chronic-phase CML as well as for imatinib-resistant or -intolerant patients. The new agent bosutinib is also classifi ed as a second-generation TKI. It targets the Bcr-Abl kinase and inhibits Scr-family kinases including Src, Lyn, and HcK. Pharmacologic data have shown that bosutinib inhibits 16 of 18 imatinib-resistant forms of Bcr-Abl kinases expressed in experiential cell lines. This agent, however, has no effect on T315I mutant cells. Ponatinib is classifi ed as a thirdgeneration TKI. The agent is unique in that it targets cells with a T315I mutation, which makes these cells resistant to all other currently approved TKIs. Medullary thyroid cancer Cabozantinib has a different indication and, therefore, targets another set of tyrosine kinases. It has been shown to inhibit proinvasive receptor tyrosine kinases implicated in tumor growth, metastasis, and angiogenesis, including RET, MET, and VEGFR-1, -2, and -3. Activating mutations in RET have been shown to play a central role in tumorigenesis in both inherited and sporadic forms of medullary thyroid cancer. MET and VEGF have also been implicated in the pathogenesis of this rare thyroid disease.