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      Intracellular Retention of ABL Kinase Inhibitors Determines Commitment to Apoptosis in CML Cells

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          Abstract

          Clinical development of imatinib in CML established continuous target inhibition as a paradigm for successful tyrosine kinase inhibitor (TKI) therapy. However, recent reports suggested that transient potent target inhibition of BCR-ABL by high-dose TKI (HD-TKI) pulse-exposure is sufficient to irreversibly commit cells to apoptosis. Here, we report a novel mechanism of prolonged intracellular TKI activity upon HD-TKI pulse-exposure (imatinib, dasatinib) in BCR-ABL-positive cells. Comprehensive mechanistic exploration revealed dramatic intracellular accumulation of TKIs which closely correlated with induction of apoptosis. Cells were rescued from apoptosis upon HD-TKI pulse either by repetitive drug wash-out or by overexpression of ABC-family drug transporters. Inhibition of ABCB1 restored sensitivity to HD-TKI pulse-exposure. Thus, our data provide evidence that intracellular drug retention crucially determines biological activity of imatinib and dasatinib. These studies may refine our current thinking on critical requirements of TKI dose and duration of target inhibition for biological activity of TKIs.

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          Most cited references38

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          Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis.

          Myelofibrosis is a Philadelphia chromosome–negative myeloproliferative neoplasm associated with cytopenias, splenomegaly, poor quality of life, and shortened survival. About half of patients with myelofibrosis carry a gain-of-function mutation in the Janus kinase 2 gene (JAK2 V617F) that contributes to the pathophysiology of the disease. INCB018424 is a potent and selective Janus kinase 1 (JAK1) and JAK2 inhibitor. We conducted a phase 1−2 trial of INCB018424 in patients with JAK2 V617F−positive or JAK2 V617F−negative primary myelofibrosis, post–essential thrombocythemia myelofibrosis, or post–polycythemia vera myelofibrosis. A total of 153 patients received INCB018424 for a median duration of more than 14.7 months. The initial dose-escalation phase established 25 mg twice daily or 100 mg once daily as maximum tolerated doses, on the basis of reversible thrombocytopenia. A dose-dependent suppression of phosphorylated signal transducer and activator of transcription 3 (STAT3), a marker of JAK signaling, was demonstrated in patients with wild-type JAK2 and in patients with the JAK2 V617F mutation. We studied additional doses and established that a 15-mg twice-daily starting dose, followed by individualized dose titration, was the most effective and safest dosing regimen. At this dose, 17 of 33 patients (52%) had a rapid objective response (≥50% reduction of splenomegaly) lasting for 12 months or more, and this therapy was associated with grade 3 or grade 4 adverse events (mainly myelosuppression) in less than 10% of patients. Patients with debilitating symptoms, including weight loss, fatigue, night sweats, and pruritus, had rapid improvement. Clinical benefits were associated with a marked diminution of levels of circulating inflammatory cytokines that are commonly elevated in myelofibrosis. INCB018424 was associated with marked and durable clinical benefits in patients with myelofibrosis for whom no approved therapies existed. (Funded by Incyte; ClinicalTrials.gov number, NCT00509899.)
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            Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays.

            A series of substituted 2-(aminopyridyl)- and 2-(aminopyrimidinyl)thiazole-5-carboxamides was identified as potent Src/Abl kinase inhibitors with excellent antiproliferative activity against hematological and solid tumor cell lines. Compound 13 was orally active in a K562 xenograft model of chronic myelogenous leukemia (CML), demonstrating complete tumor regressions and low toxicity at multiple dose levels. On the basis of its robust in vivo activity and favorable pharmacokinetic profile, 13 was selected for additional characterization for oncology indications.
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              Overriding imatinib resistance with a novel ABL kinase inhibitor.

              Resistance to the ABL kinase inhibitor imatinib (STI571 or Gleevec) in chronic myeloid leukemia (CML) occurs through selection for tumor cells harboring BCR-ABL kinase domain point mutations that interfere with drug binding. Crystallographic studies predict that most imatinib-resistant mutants should remain sensitive to inhibitors that bind ABL with less stringent conformational requirements. BMS-354825 is an orally bioavailable ABL kinase inhibitor with two-log increased potency relative to imatinib that retains activity against 14 of 15 imatinib-resistant BCR-ABL mutants. BMS-354825 prolongs survival of mice with BCR-ABL-driven disease and inhibits proliferation of BCR-ABL-positive bone marrow progenitor cells from patients with imatinib-sensitive and imatinib-resistant CML. These data illustrate how molecular insight into kinase inhibitor resistance can guide the design of second-generation targeted therapies.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                16 July 2012
                : 7
                : 7
                : e40853
                Affiliations
                [1 ]Department of Hematology and Oncology, University Medical Center, Otto-von-Guericke-University, Magdeburg, Germany
                [2 ]Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany
                [3 ]Institute of Forensic Medicine, University Medical Center, Otto-von-Guericke-University, Magdeburg, Germany
                [4 ]Department of Medicine A (Hematology, Oncology and Pneumology), University of Münster, Münster, Germany
                [5 ]Department of Oncology, Hematology and Stem Cell Transplantation, University Medical Center, Rheinisch-Westfaelische Technische Hochschule, Aachen, Germany
                [6 ]Department of Haematology, Centre for Cancer Biology, University of Adelaide, Adelaide, Australia
                [7 ]Department of Haematology, Imperial College London, London, United Kingdom
                [8 ]Third Department of Medicine, University Medical Center, Johannes Gutenberg-University, Mainz, Germany
                Mayo Clinic College of Medicine, United States of America
                Author notes

                Conceived and designed the experiments: DBL TF. Performed the experiments: MCW MD TS. Analyzed the data: DBL MCW FH TK TF. Wrote the paper: DBL MCW FH TK TF. Performed and analyzed TKI measurements and wrote “HPLC measurements of TKIs” in Materials and Methods: MD. Provided reagents and participated in writing the paper: JVM. Designed and analyzed radioactive drug-uptake and drug-release experiments and participated in writing the paper: MS CMT SK.

                Article
                PONE-D-12-11767
                10.1371/journal.pone.0040853
                3397954
                22815843
                bbdde74b-c005-48ed-9b4f-abc0002d61a8
                Lipka et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 23 April 2012
                : 14 June 2012
                Page count
                Pages: 16
                Categories
                Research Article
                Medicine
                Drugs and Devices
                Drug Research and Development
                Pharmacodynamics
                Hematology
                Hematologic Cancers and Related Disorders
                Leukemias
                Chronic Myeloid Leukemia
                Myeloproliferative Disorders

                Uncategorized
                Uncategorized

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