This disease is caused by the reciprocal translocation, t(9;22)(q34;q11), involving chromosomes 9 and 22 which results in fusion of BCR and ABL1 genes. Because of this translocation, a novel, BCR-ABL fusion gene is created which results in expression of the constitutively active tyrosine kinase BCR-ABL protein.The constitutive activity of this tyrosine kinase plays a central role in the pathogenesis of the disease. The expression of chimeric BCR-ABL protein with deregulated tyrosine kinase activity has been shown to be necessary and enough for the transformed phenotype of CML cells.
IMATINIB MESYLATE
Imatinib mesylate (IM), the molecular targeted drug for the treatment of all phases of CML is a 2-phenylaminopyrimidine derivative that works by binding to the tyrosine kinase domain of BCR-ABL and blocking its function.
DEVELOPMENT OF RESISTANCE TO IMATINIB MESYLATE
Targeted inhibition of BCRABL kinase with IM has become the frontline therapy for newly diagnosed patients with CML and other leukemias that express BCRABL kinase. Despite the successful treatment results obtained with IM, achievement of prolonged response to IM is still a daunting problem, the chief obstacle being development of resistance to IM in a significant proportion of patients. Some of the chronic phase CML patients and most of the CML patients with late stage (accelerated or blast phase) develop resistance to IM and the disease progresses creating concern in the treatment of CML.
Among the multiple mechanisms of resistance identified, the dominant mechanism appears to be acquisition of point mutations in the kinase domain of BCR-ABL which results in altered affinity of IM for the BCR-ABL1 protein.
BCR-ABL mutations had been reported to occur in approximately 50% of patients who develop resistance to IM. Defining the mechanisms of resistance in large number of patients is the best option to begin with the clinical efforts to overcome IM resistance.