Imatinib Resistance: Obstacles and Opportunities

Abstract

Abstract Objective.—To review the current status of resistance to imatinib mesylate (IM) in patients with chronic myelogenous leukemia, and the obstacles and opportunities presented by the development of this resistance. Data Sources and Study Selection.—Review of selected studies obtained from a MEDLINE search encompassing the years 1950 to 2004. Data Extraction and Data Synthesis.—Relevant information from the selected studies was abstracted and summarized. Conclusions.—The identification of the Philadelphia chromosome and the subsequent discovery that it represents a translocation between the long arms of chromosomes 9 and 22 producing an aberrant tyrosine kinase, known as BCR-ABL1, has catalyzed our understanding and treatment of this hematologic malignancy. An extensive search for molecules to block the aberrant BCR-ABL1 protein resulted in the development of IM as an orally bioavailable agent with remarkable efficacy in producing hematologic, cytogenetic, and molecular remissions. However, follow-up of patients treated with IM has demonstrated that some patients can develop resistance to IM with progression of their leukemia. Multiple mechanisms of resistance have been identified. The dominant mechanism appears to be mutations in the kinase domain of BCR-ABL1, which result in altered affinity of IM for the BCR-ABL1 protein. Recently, small-molecule, combined SRC and ABL1 inhibitors have been developed and entered into clinical trials. These inhibitors appear effective in inhibiting most of the mutant BCR-ABL1 molecules that are resistant to IM. The rapid development of new therapies for treatment of chronic myelogenous leukemia brings the promise that this disorder can be cured or controlled in many patients with oral drugs that have a low toxicity profile.