Tyrosine kinase inhibitors: the first decade.
ABSTRACT The treatment of chronic myeloid leukemia (CML) drastically changed with the introduction of imatinib mesylate, a Bcr-Abl1 tyrosine kinase inhibitor (TKI), in 1998. By directly targeting this leukemogenic protein kinase, imatinib affords patients with CML sustained chromosomal remissions, which translate into prolonged survival. However, there has been concern over the emergence of resistance to imatinib, and some patients fail to respond or are intolerant of imatinib therapy because of untoward toxicity. This has spurred interest in developing novel TKIs to overcome the mechanisms of resistance that lead to treatment failure-most importantly, Bcr-Abl1 kinase domain mutations. Two of these second-generation TKIs, nilotinib and dasatinib, are approved worldwide for the treatment of CML after imatinib failure or intolerance. Although these agents are active, they fail in many patients because of the development of highly resistant mutations such as the T315I, against which several novel agents are currently being tested in clinical trials. This review provides an account of the progress made in the field of TKI therapy for CML over the past decade.
- SourceAvailable from: sciencedirect.com[Show abstract] [Hide abstract]
ABSTRACT: The pathognomonic genetic alteration in chronic myeloid leukemia is the formation of the BCR-ABL1 fusion gene, which produces a constitutively active tyrosine kinase that drives leukemic transformation. Targeted tyrosine kinase inhibitor treatment with imatinib, nilotinib, dasatinib, bosutinib, and ponatinib is the cornerstone of modern therapy for this hematological malignancy. Real-time quantitative RT-PCR (RT-qPCR) of BCR-ABL1 RNA is a necessary laboratory technique for monitoring the efficacy of tyrosine kinase inhibitor therapy and quantitatively assessing minimal residual disease. The molecular response measured by BCR-ABL1 RT-qPCR assists in identifying suboptimal responses and can help inform the decision to switch to alternative therapies that may be more efficacious (or to pursue more stringent monitoring). Furthermore, the tyrosine kinase inhibitor-mediated molecular response provides valuable risk stratification and prognostic information on long-term outcomes. Despite these attributes, informed, universal, practical utilization of this well-established monitoring test will require heightened efforts by the molecular diagnostics laboratory community to adopt the standardized reporting units of the International Scale. Without widespread adoption of the International Scale, the consensus major molecular response and early molecular response treatment thresholds will not be definable, and optimal clinical outcomes for patients with chronic myeloid leukemia may not be achieved.The Journal of molecular diagnostics: JMD 06/2013; · 3.48 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Hedgehog signaling is a driving force in medulloblastoma and basal cell carcinoma (BCC), making it an attractive therapeutic target. Vismodegib recently received FDA approval for the treatment of inoperable BCC, but a drug-resistant Smoothened (Smo) mutant (D473H) was identified in a clinical study. TAK-441 is a pyrrolo[3,2-c]pyridine-4-one derivative that potently inhibits Hh signal transduction and is currently under investigation in clinical trials. We demonstrated that TAK-441 inhibits reporter activity in D473H-transfected cells with an IC50 of 79nM, while Vismodegib showed an IC50=7,100nM. In order to investigate the mode of inhibition, we evaluated the Smo inhibitors with three different binding assays, such as [(3)H]-TAK-441 membrane binding assay, affinity selection-MS detection assay, and bodipy-cylopamine whole cell assay. In three different assays, Vismodegib and cyclopamine showed lower affinity for the D473H mutant in comparison with wild-type Smo. On the other hand, TAK-441 showed almost equal binding affinity for the D473H mutant compared with wild-type Smo in the binding assays, although TAK-441 binds to the same binding site as two other well-known inhibitors. These in vitro findings suggest that TAK-441 has the potential for clinical use in cancers that are dependent on Hedgehog signaling, including wild-type tumors and Vismodegib-resistant D473H mutants.European journal of pharmacology 11/2013; · 2.59 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Tyrosine kinase inhibitors (TKIs) have dramatically improved the outcome of chronic myeloid leukemia (CML). Even though TKI therapy does not necessarily eliminate all leukemic cells, a small proportion of CML patients is able to discontinue the treatment successfully and be considered cured. Besides inhibiting the actual target BCR-ABL1 kinase in leukemic cells, TKIs inhibit several off-target kinases in normal healthy cells, such as lymphocytes. To date, little is known about the long-term in vivo effects of TKI treatment on the function of the immune system. However, constantly growing evidence suggests that some TKIs have a dual-mode of action; the direct cytotoxic effects induced by oncokinase inhibition are accompanied by the activation of immune system 2 , which is potentially relevant for the long-term control of CML. In this review, we have summarized the reported immunomodulatory effects of the three TKIs, which currently are accepted for first-line use in CML (imatinib, dasatinib and nilotinib). Understanding the mechanisms of TKI-induced functional cure and the role of immune system in this process will hopefully not only benefit CML patients, but also patients with other malignant diseases in the future.07/2013;