Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical studies have shown that the tyrosine kinase inhibitor STI571 effectively controls BCR-ABL-positive chronic myelogenous leukemia (CML). However, disease progression while on STI571 therapy has been reported, suggesting de novo or intrinsic resistance to BCR-ABL-targeted therapy. To investigate possible mediators of acquired STI571 resistance, K562 cells resistant to 5 microM STI571 (K562-R) were cloned and compared to the parental cell population. K562-R cells had reduced BCR-ABL expression and limited activation of BCR-ABL signaling cascades (Stat 5, CrkL, MAPK). STI571 failed to activate caspase cascades or to suppress expression of survival genes (bcl-xL) in resistant cells. Gene sequencing and tyrosine kinase activity measurements demonstrated that K562-R cells retained wild-type and active BCR-ABL tyrosine kinase that was inhibitable by in vitro incubation with STI571, suggesting that BCR-ABL was not coupled to proliferation or survival of K562-R cells. The src-related kinase LYN was highly overexpressed and activated in K562-R cells, and its inhibition reduced proliferation and survival of K562-R cells while having limited effects of K562 cells. Specimens taken from patients with advanced CML that progressed on STI571 therapy also were analyzed for LYN kinase expression, and they were found to be elevated to a level similar to that of K562-R cells. Comparison of samples from patients taken prior to and following STI571 failure suggested that expression and/or activation of LYN/HCK occurs during disease progression. Together, these results suggest that acquired STI571 resistance may be associated with BCR-ABL independence and mediated in part through overexpression of other tyrosine kinases.
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PMID:BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. 1250 83

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.
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PMID:Overcoming kinase resistance in chronic myeloid leukemia. 1840 81

Dasatinib is a second-generation tyrosine kinase inhibitor (TKI) for chronic, blastic, or accelerated phase chronic myeloid leukemia (CML) patients who are resistant or intolerant to previous treatment. It potently inhibits BCR/ABL and SRC-family kinases (SRC, LCK, HCK, YES, FYN, FGR, BLK, LYN, FRK), as well as c-KIT, PDGFR-a and -b, and ephrin receptor kinase. Various clinical trials have provided evidence that it has more durable complete hematologic and cytogenetic responses, as well as more potency in imatinib-resistant or -intolerant CML, and it has also shown its advantages in newly diagnosed CML compared to imatinib. In this review, we mainly focus on the structure, mechanisms, pharmacokinetics, and pharmacogenetics of dasatinib. We also summarize clinical trials with dasatinib on CML and provide our recommendations for dasatinib in the treatment of CML.
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PMID:The role of dasatinib in the management of chronic myeloid leukemia. 2570 1