Overcoming kinase resistance in chronic myeloid leukemia.
Imatinib is a small-molecule inhibitor of BCR-ABL tyrosine kinase activity, with proven efficacy and tolerability. Despite imatinib's activity, the development of resistance, whether BCR-ABL dependent or independent, is a concern. BCR-ABL-dependent resistance is commonly a result of mutations in the BCR-ABL gene, which can induce a structural predisposition towards the active conformation of the protein, resulting in a shift in the equilibrium of BCR-ABL from inactive, which imatinib binds, to active, which imatinib is unable to bind. BCR-ABL gene amplification may play a role in the development of imatinib resistance in patients with CML. There are a number of BCR-ABL-independent mechanisms of imatinib resistance, including the efflux protein multidrug resistance protein-1, of which imatinib is a substrate. Another mechanism may be the development of alternative pathways of disease progression, leading to less reliance on BCR-ABL; indeed, the SRC family tyrosine kinases LYN and HCK have been frequently implicated in treatment resistance and progression of CML. Clearly, imatinib resistance requires the development of other treatment options. Dasatinib, with increased binding potency (325-fold greater potency than imatinib for wild-type BCR-ABL), inhibition of both the active and inactive formation of BCR-ABL, and targeting of SRC family kinases, is the only agent approved for the treatment of patients with imatinib-resistant or -intolerant CML and Ph+ ALL. Dasatinib is highly active in all phases of these diseases, and is active in the majority of imatinib-resistant mutations, with the exception of T315I. The development of agents that effectively inhibit T315I mutations suggests that future treatment options will include combination therapy.
Lee
Francis
F
Bristol-Myers Squibb, 206 Provence Line Road, Princeton, NJ 08543, USA. francis.lee@bms.com
Fandi
Abderrahim
A
Voi
Maurizio
M
D001549:Benzamides; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D016313:Genes, abl; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D009154:Mutation; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib