Overcoming kinase resistance in chronic myeloid leukemia.

摘要: Imatinib is a small-molecule inhibitor of BCR-ABL tyrosine kinase activity, with proven efficacy and tolerability. Despite imatinib's the development resistance, whether dependent or independent, concern. BCR-ABL-dependent resistance commonly result mutations in gene, which can induce structural predisposition towards active conformation protein, resulting shift equilibrium from inactive, imatinib binds, to active, unable bind. gene amplification may play role patients CML. There are number BCR-ABL-independent mechanisms including efflux protein multidrug protein-1, substrate. Another mechanism be alternative pathways disease progression, leading less reliance on BCR-ABL; indeed, SRC family kinases LYN HCK have been frequently implicated treatment progression Clearly, requires other options. Dasatinib, increased binding potency (325-fold greater than for wild-type BCR-ABL), inhibition both inactive formation BCR-ABL, targeting kinases, only agent approved imatinib-resistant -intolerant CML Ph+ ALL. Dasatinib highly all phases these diseases, majority mutations, exception T315I. The agents that effectively inhibit T315I suggests future options will include combination therapy.