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1 Howard Hughes Medical Institute and 2 Division of Hematology and Medical Oncology, Oregon Health and Science University Cancer Institute; 3 Portland Veterans Affairs Medical Center, Portland, Oregon; 4 Novartis Institutes for Biomedical Research, Basel, Switzerland; and 5 Bristol-Myers Squibb Oncology, Princeton, New Jersey
Requests for reprints: Thomas O'Hare, Howard Hughes Medical Institute, Oregon Health and Science University, L592, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239. Phone: 503-494-5596; Fax: 503-494-3688; E-mail: oharet{at}ohsu.edu.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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In patients who relapse on imatinib therapy, the Bcr-Abl kinase is reactivated, emphasizing the importance of the kinase activity of this protein to disease pathogenesis. The most common mechanism of resistance, occurring in 60% to 90% of patients who acquire imatinib resistance, involves specific mutations in the kinase domain of Bcr-Abl that interfere with imatinib binding without eliminating ATP binding or kinase activity (reviewed in refs. 7, 8). Clinically observed mutations identified within the Bcr-Abl kinase domain span a range of residual imatinib sensitivities (IC50: 900-4,400 nmol/L) and encompass several functionally distinct kinase domain regions, including the nucleotide binding P-loop, imatinib contact residues, and the activation loop (7, 9, 10).
An understanding of the mechanism of imatinib resistance has prompted the search for alternate Bcr-Abl inhibitors that are effective against clinically observed Bcr-Abl mutants. Two promising new Bcr-Abl inhibitors for treating imatinib-resistant CML are currently being evaluated in clinical trials: the selective Abl inhibitor AMN107 and the dual Src/Abl inhibitor BMS-354825 (Fig. 1A, top). AMN107 was developed by rational drug design based on the crystal structure of an Abl-imatinib complex, whereas BMS-354825 is a Src inhibitor that was found to exhibit Abl inhibitory properties.
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Another approach to counteract imatinib resistance is to use inhibitors that bind Bcr-Abl with less stringent conformational requirements than imatinib. Imatinib selectively targets an inactive conformation of the Abl kinase domain in which the activation loop is in a nonphosphorylated, closed position that is incompatible with substrate binding (13). Specific differences between the inactive conformations of Abl and Src provide a structural basis for the initially surprising finding that Src family kinases are not imatinib targets, despite a high degree of sequence homology (11). The Abl and Src active conformations are more similar and many inhibitors that bind to the active conformation of Src are also capable of inhibiting Abl (11). BMS-354825 is a dual Src-Abl kinase inhibitor that inhibits all tested Bcr-Abl kinase domain mutants observed in relapsed patients with the exception of T315I. The drug was also highly effective in a mouse model of imatinib-resistant, Bcr-Abl–dependent disease (14).
Although some data regarding the ability of AMN107 to inhibit various imatinib-resistant mutants is available, a number of the common mutants have not been included in the published data. Further, given differences in cell lines used, variations in levels of Bcr-Abl expression, and differing assay conditions, a direct comparison of AMN107 and BMS-354825 based on published results is not possible. Given that both of these drugs are in clinical trials, knowledge of the relative sensitivity of a particular mutant could assist in determining which drug would be more appropriate for a particular patient. Therefore, in this report, we present a complete profile of AMN107 against imatinib-resistant mutants and a direct cellular and biochemical comparison between imatinib, AMN107, and BMS-354825
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Materials and Methods |
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Cell lines. Ba/F3 transfectants (expressing full-length wild-type Bcr-Abl or Bcr-Abl with kinase domain point mutations) were generated, selected, and maintained as previously described (10). Parental Ba/F3 cells were supplemented with interleukin-3 (IL-3).
Kinase autophosphorylation assays with glutathione S-transferase–Abl kinase domains. Kinase assays using wild-type and mutant glutathione S-transferase (GST)–Abl fusion proteins (c-Abl amino acids 220-498) were done as described, with minor alterations (15). GST-Abl fusion proteins were released from glutathione-Sepharose beads before use; the concentration of ATP was 5 µmol/L. Immediately before use in kinase autophosphorylation and in vitro peptide substrate phosphorylation assays, GST-Abl kinase domain fusion proteins were treated with LAR tyrosine phosphatase according to the manufacturer's instructions (New England Biolabs, Beverly, MA). After 1-hour incubation at 30°C, LAR phosphatase was inactivated by addition of sodium vanadate (1 mmol/L). Immunoblot analysis comparing untreated GST-Abl kinase to dephosphorylated GST-Abl kinase was routinely done using phosphotyrosine-specific antibody 4G10 to confirm complete (>95%) dephosphorylation of tyrosine residues and c-Abl antibody CST 2862 to confirm equal loading of GST-Abl kinase. The inhibitor concentration ranges for IC50 determinations were 0 to 5,000 nmol/L (imatinib and AMN107) or 0 to 32 nmol/L (BMS-354825). The BMS-354825 concentration range was extended to 1,000 nmol/L for mutant T315I. These same inhibitor concentrations were used for the in vitro peptide substrate phosphorylation assays. The three inhibitors were tested over these same concentration ranges against GST-Src kinase (Cell Signaling Technology, Boulder, CO) and GST-Lyn kinase (Stressgen, Victoria, BC, Canada).
In vitro peptide substrate phosphorylation assays with glutathione S-transferase–Abl kinase domains. The effects of imatinib (0-5,000 nmol/L), AMN107 (0-5,000 nmol/L), and BMS-354825 (0-32 nmol/L) on the catalytic activity of unphosphorylated GST-Abl kinase were assessed using a synthetic, NH2-terminal biotin-linked peptide substrate (biotin-EAIYAAPFAKKK-amide; ref. 16). Assays were carried out at 30°C for 5 minutes in 25 µL of reaction mixture consisting of kinase buffer [25 mmol/L Tris-HCl (pH 7.5), 5 mmol/L ß-glycerophosphate, 2 mmol/L DTT, 0.1 mmol/L Na3VO4, 10 mmol/L MgCl2; Cell Signaling Technology], 50 µmol/L peptide substrate, 10 nmol/L wild-type or mutant GST-Abl kinase, and 50 µmol/L ATP/[
-32P]ATP (5,000 cpm/pmol). Reactions were terminated by addition of guanidine hydrochloride to a final concentration of 2.5 mol/L. A portion of each terminated reaction mixture was transferred to a streptavidin-coated membrane (SAM2 biotin capture membrane; Promega, Madison, WI), washed, and dried according to the manufacturer's instructions; phosphate incorporation was determined by scintillation counting. Results were corrected for background binding to the membranes as determined by omitting peptide substrate from the kinase reaction. Time course experiments to establish the linear range of enzymatic activity preceded kinase assays. Similar in vitro peptide substrate phosphorylation assays were conducted with two Src family kinases: GST-Src kinase (Cell Signaling Technology) and GST-Lyn kinase (Stressgen). For Src family kinases, SignaTECT PTK biotinylated peptide substrate 2 (Promega) was the peptide substrate; all other conditions were as described for the GST-Abl kinase assays.
Cellular proliferation assays. Ba/F3 cell lines were plated in triplicate and incubated with escalating concentrations of imatinib, AMN107, or BMS-354825 for 72 hours. Proliferation was measured using a methanethiosulfonate-based viability assay (CellTiter96 Aqueous One Solution Reagent; Promega). IC50 and IC90 values are reported as the mean of three independent experiments done in quadruplicate. The inhibitor concentration ranges for IC50 and IC90 determinations were 0 to 2,000 nmol/L (imatinib and AMN107) or 0 to 32 nmol/L (BMS-354825). The imatinib concentration range was extended to 6,400 nmol/L for mutants with IC50 >2,000 nmol/L. The BMS-354825 concentration range was extended to 200 nmol/L for mutant T315I.
Immunoblotting. Ba/F3 cell lines (1 x 106 cells) were incubated for 3 hours in media containing escalating doses of either imatinib or AMN107. Cells were collected by centrifugation and lysed in SDS sample buffer. Following SDS-PAGE, proteins were transferred to Immobilon-P membranes (Millipore Corp., Bedford, MA) for immunoblotting. Tyrosine-phosphorylated Bcr-Abl was detected with mouse monoclonal phosphotyrosine antibody 4G10 (Supplementary Fig. S1). Bcr-Abl expression was detected using rabbit c-Abl antibody CST 2862 (Cell Signaling Technology).
Apoptosis assays. Ba/F3 cell lines (6 x 104 cells/well) were incubated in 1 mL media containing vehicle, imatinib (300 nmol/L, 1,500 nmol/L), or AMN107 (30, 300, and 1,500 nmol/L) for 72 hours. Detection of apoptosis was done using a Guava Nexin apoptosis kit (Annexin V-phycoerythrin and 7-amino-actinomycin D; Guava Technologies, Hayward, CA) and a Guava Technologies PCA instrument. Results based on three independent experiments are reported as the mean ± SE (Supplementary Fig. S2).
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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20-fold higher potency than imatinib (IC50: 15 versus 280 nmol/L), whereas BMS-354825 had a two-log (325-fold) increased potency relative to imatinib (IC50: 0.6 versus 280 nmol/L). Corresponding experiments with mutant Abl kinase domains revealed that the 20-fold improved potency of AMN107 compared with imatinib is also seen with the imatinib-resistant mutants (Table 1). The one exception was the Abl mutant T315I, which was completely insensitive to AMN107 (highest concentration tested: 5,000 nmol/L). To facilitate comparisons within Table 1, the IC50 data are also expressed as fold change relative to a baseline of one for wild-type Abl kinase. By viewing the data in this way, it is apparent that the overall pattern of mutant sensitivity to AMN107 closely parallels that of imatinib. Because imatinib and AMN107 are predicted to share an absolute requirement for a specific inactive Bcr-Abl conformation and to bind in very similar ways, it is logical to expect largely the same pattern of effectiveness for AMN107 as for imatinib, but with the range of effectiveness shifted to a value more than an order of magnitude lower than that of imatinib. In contrast, BMS-354825 potently inhibited wild-type Abl kinase and all mutants except T315I over a narrow range (IC50 
1.7 nmol/L). We also did a complete set of Abl kinase autophosphorylation assays with each of the inhibitors and obtained similar results to those from peptide substrate assays (Table 1). Thus, biochemical assays establish that AMN107 and BMS-354825 directly target wild-type and mutant Abl kinase domains and inhibit autophosphorylation and substrate phosphorylation in a concentration-dependent manner. Similar assays with the Src family kinases Src and Lyn (17, 18), which is expressed at high levels in primary CML blast crisis cells, showed that BMS-354825 is a potent inhibitor of these Src family kinases, whereas imatinib and AMN107 are inactive against these kinases (Table 1).
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70 nmol/L: M244V, G250E, Q252H, F3llL, F317L, M351T, V379I, L387M, H396P, H396R), medium (IC50 200 nmol/L: Y253F, E255K, F359V), low (IC50 450 nmol/L: Y253H, E255V), and insensitive (IC50 > 2 µmol/L: T315I). This pattern is highly reminiscent of the corresponding ranking of imatinib sensitivities (Table 2) and expected given the highly related structures of these two compounds and the binding constraints they share. However, there are a few differences in the fold differences in sensitivities of the mutants to imatinib and AMN107. This is particularly noteworthy for M351T. Due to the structural differences between AMN107 and imatinib, this residue comes in close proximity to imatinib, but is less critical for coordinating binding of AMN107. BMS-354825, on the other hand, was found to be an extremely potent inhibitor of proliferation in cells expressing all mutants except T315I. As in the biochemical assays, the range of IC50 values for cells treated with BMS-354825 was narrow (0.8-11 nmol/L), in line with the proposal that the Bcr-Abl structural requirements for binding BMS-354825 are much less stringent than for imatinib family members.
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In agreement with cellular proliferation and tyrosine phosphorylation assay results, AMN107 induced apoptosis at significantly lower concentrations than imatinib in cells expressing wild-type Bcr-Abl or any of the kinase domain mutants except T315I (Supplementary Fig. S2). At the highest AMN107 concentration tested (1.5 µmol/L), >90% of the cells were Annexin positive except in the cases of Y253H (65%), E255V (65%), and T315I (3%). Parental Ba/F3 cells and Ba/F3 cells expressing Bcr-Abl mutant T315I did not undergo apoptosis above vehicle-treated control levels in response to either inhibitor.
A conservative estimate for imatinib steady-state trough levels in patients treated with 400 mg imatinib per day is 1.5 µmol/L (2, 20). The pharmacokinetic profile and maximum tolerated dose for AMN107 have not been reported, and its effectiveness as a therapy for imatinib-resistant CML will depend on the concentration that can be reached in humans. Preliminary findings from the phase I/II study indicate that orally administered AMN107 at 200 mg per day is well tolerated with biological and marrow effects in some patients (21). Taking inhibition at or above the IC90 value (Table 2) as a benchmark for clinical benefit, AMN107 at a trough level of 1.5 µmol/L would be predicted to be an effective single agent therapeutic for cells expressing wild-type Bcr-Abl and all mutants tested except T315I. If a trough level of only 500 nmol/L is achievable, three mutants (Y253H, E255V, and T315I) are predicted to be substantially resistant.
BMS-354825 is 325-fold more potent than imatinib and 16-fold more potent than AMN107 against wild-type Bcr-Abl. Again, invoking inhibition at or above the IC90 value (Table 2) as an indicator of clinical benefit, BMS-354825 would be predicted to be an effective single agent therapeutic for cells expressing wild-type Bcr-Abl and all mutants tested except T315I at a trough level of 50 nmol/L. Establishing and utilizing the minimum effective concentration may be especially important in the case of dual Src/Abl inhibitors, such as BMS-354825 due to concerns pertaining to off-target effects.
In summary, the cellular and biochemical experiments directly comparing AMN107 and BMS-354825 to imatinib show that both inhibitors are more potent than imatinib against all cell lines and purified Abl kinase domains tested except T315I. The mutants, other than T315I, that were least responsive to AMN107 in all three cellular assays were Y253H and E255V (Fig. 2). Analogous to imatinib, the extent of sensitivity to AMN107 depended on the specific substitution at a given position (e.g., E255V less sensitive than E255K to AMN107).
Both AMN107 and BMS-354825 hold promise for treating patients with imatinib-resistant CML except when the disease is driven by Bcr-Abl mutant T315I. Although both inhibitors efficiently block Bcr-Abl tyrosine kinase catalytic activity, they do so by binding to distinct, partially overlapping sites in the kinase domain and by placing different conformational requirements on the Abl kinase domain. If results of clinical trials and pharmacokinetic studies indicate that AMN107 and BMS-354825 are safe and effective, the feasibility of using these drugs in combination should be evaluated. In support of this approach, we recently investigated the use of imatinib in combination with BMS-354825 as a strategy for confronting drug resistance in CML.6 Specifically, treating Ba/F3 cells expressing wild-type or imatinib-resistant Bcr-Abl kinase domain mutants with various combinations of imatinib and BMS-354825 produced additive inhibitory effects. Even at imatinib concentrations above clinically achievable levels, no antagonism of the Src/Abl inhibitor was observed. A particularly appealing therapeutic option is to use a Bcr-Abl inhibitor cocktail containing these inhibitors as well as an as yet undiscovered T315I inhibitor. Advantages of combinatorial therapy are that clones resistant to one of the Bcr-Abl inhibitors may be vulnerable to another component of the cocktail (22), the potential to eliminate a wider spectrum of mutants, including those that predate therapeutic intervention (23), and eradication of a higher proportion of residual leukemic cells (8). Therefore, using Bcr-Abl inhibitor combinations to treat newly diagnosed, chronic-phase CML patients may represent the best strategy to prevent or significantly delay the onset of acquired drug resistance. In addition, these Bcr-Abl kinase inhibitors could also increase response rates and duration of response due to their increased potency.
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Acknowledgments |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
We thank Amie Corbin for providing the GST-Abl kinase domain constructs used for enzymatic assays.
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Footnotes |
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T. O'Hare and D.K. Walters contributed equally to this work.
6 T. O'Hare, et al. Combined Abl inhibitor therapy for minimizing drug resistance in CML: Src/Abl inhibitors are compatible with imatinib, submitted for publication. 
Received 1/25/05. Revised 3/28/05. Accepted 4/ 7/05.
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T. Trowe, S. Boukouvala, K. Calkins, R. E. Cutler Jr., R. Fong, R. Funke, S. B. Gendreau, Y. D. Kim, N. Miller, J. R. Woolfrey, et al. EXEL-7647 Inhibits Mutant Forms of ErbB2 Associated with Lapatinib Resistance and Neoplastic Transformation Clin. Cancer Res., April 15, 2008; 14(8): 2465 - 2475. [Abstract] [Full Text] [PDF]
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A. Gontarewicz, S. Balabanov, G. Keller, R. Colombo, A. Graziano, E. Pesenti, D. Benten, C. Bokemeyer, W. Fiedler, J. Moll, et al. Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I Blood, April 15, 2008; 111(8): 4355 - 4364. [Abstract] [Full Text] [PDF]
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 L. K. Kenealy, C. B. Christenson, and C. B. Williams Current Therapies for Chronic Myeloid Leukemia Journal of Pharmacy Practice, April 1, 2008; 21(2): 116 - 125. [Abstract] [PDF]
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N. Godin-Heymann, L. Ulkus, B. W. Brannigan, U. McDermott, J. Lamb, S. Maheswaran, J. Settleman, and D. A. Haber The T790M "gatekeeper" mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor Mol. Cancer Ther., April 1, 2008; 7(4): 874 - 879. [Abstract] [Full Text] [PDF]
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T. Fojo Commentary: Novel Therapies for Cancer: Why Dirty Might Be Better Oncologist, March 1, 2008; 13(3): 277 - 283. [Full Text] [PDF]
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J. S. Khorashad, D. Milojkovic, P. Mehta, M. Anand, S. Ghorashian, A. G. Reid, V. De Melo, A. Babb, H. de Lavallade, E. Olavarria, et al. In vivo kinetics of kinase domain mutations in CML patients treated with dasatinib after failing imatinib Blood, February 15, 2008; 111(4): 2378 - 2381. [Abstract] [Full Text] [PDF]
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P. le Coutre, O. G. Ottmann, F. Giles, D.-W. Kim, J. Cortes, N. Gattermann, J. F. Apperley, R. A. Larson, E. Abruzzese, S. G. O'Brien, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia Blood, February 15, 2008; 111(4): 1834 - 1839. [Abstract] [Full Text] [PDF]
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H. Kantarjian, C. Schiffer, D. Jones, and J. Cortes Monitoring the response and course of chronic myeloid leukemia in the modern era of BCR-ABL tyrosine kinase inhibitors: practical advice on the use and interpretation of monitoring methods Blood, February 15, 2008; 111(4): 1774 - 1780. [Full Text] [PDF]
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M. Baccarani, F. Pane, and G. Saglio Monitoring treatment of chronic myeloid leukemia Haematologica, February 1, 2008; 93(2): 161 - 169. [Full Text] [PDF]
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J. Cortes, E. Jabbour, H. Kantarjian, C. C. Yin, J. Shan, S. O'Brien, G. Garcia-Manero, F. Giles, M. Breeden, N. Reeves, et al. Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors Blood, December 1, 2007; 110(12): 4005 - 4011. [Abstract] [Full Text] [PDF]
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H. M. Kantarjian, F. Giles, N. Gattermann, K. Bhalla, G. Alimena, F. Palandri, G. J. Ossenkoppele, F.-E. Nicolini, S. G. O'Brien, M. Litzow, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance Blood, November 15, 2007; 110(10): 3540 - 3546. [Abstract] [Full Text] [PDF]
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O. Ottmann, H. Dombret, G. Martinelli, B. Simonsson, F. Guilhot, R. A. Larson, G. Rege-Cambrin, J. Radich, A. Hochhaus, A. M. Apanovitch, et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study Blood, October 1, 2007; 110(7): 2309 - 2315. [Abstract] [Full Text] [PDF]
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T. O'Hare, C. A. Eide, and M. W. N. Deininger Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia Blood, October 1, 2007; 110(7): 2242 - 2249. [Abstract] [Full Text] [PDF]
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O. Hantschel, U. Rix, U. Schmidt, T. Burckstummer, M. Kneidinger, G. Schutze, J. Colinge, K. L. Bennett, W. Ellmeier, P. Valent, et al. The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib PNAS, August 14, 2007; 104(33): 13283 - 13288. [Abstract] [Full Text] [PDF]
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G. Dasmahapatra, N. Yerram, Y. Dai, P. Dent, and S. Grant Synergistic Interactions between Vorinostat and Sorafenib in Chronic Myelogenous Leukemia Cells Involve Mcl-1 and p21CIP1 Down-Regulation Clin. Cancer Res., July 15, 2007; 13(14): 4280 - 4290. [Abstract] [Full Text] [PDF]
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H. Pfeifer, B. Wassmann, A. Pavlova, L. Wunderle, J. Oldenburg, A. Binckebanck, T. Lange, A. Hochhaus, S. Wystub, P. Bruck, et al. Kinase domain mutations of BCR-ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) Blood, July 15, 2007; 110(2): 727 - 734. [Abstract] [Full Text] [PDF]
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A. Ray, S. W. Cowan-Jacob, P. W. Manley, J. Mestan, and J. D. Griffin Identification of BCR-ABL point mutations conferring resistance to the Abl kinase inhibitor AMN107 (nilotinib) by a random mutagenesis study Blood, June 1, 2007; 109(11): 5011 - 5015. [Abstract] [Full Text] [PDF]
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F. Guilhot, J. Apperley, D.-W. Kim, E. O. Bullorsky, M. Baccarani, G. J. Roboz, S. Amadori, C. A. de Souza, J. H. Lipton, A. Hochhaus, et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase Blood, May 15, 2007; 109(10): 4143 - 4150. [Abstract] [Full Text] [PDF]
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X. Jiang, K. M. Saw, A. Eaves, and C. Eaves Instability of BCR-ABL Gene in Primary and Cultured Chronic Myeloid Leukemia Stem Cells J Natl Cancer Inst, May 2, 2007; 99(9): 680 - 693. [Abstract] [Full Text] [PDF]
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H. G. Jorgensen, E. K. Allan, N. E. Jordanides, J. C. Mountford, and T. L. Holyoake Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells Blood, May 1, 2007; 109(9): 4016 - 4019. [Abstract] [Full Text] [PDF]
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J. Cortes, P. Rousselot, D.-W. Kim, E. Ritchie, N. Hamerschlak, S. Coutre, A. Hochhaus, F. Guilhot, G. Saglio, J. Apperley, et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis Blood, April 15, 2007; 109(8): 3207 - 3213. [Abstract] [Full Text] [PDF]
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S. Nam, A. Williams, A. Vultur, A. List, K. Bhalla, D. Smith, F. Y. Lee, and R. Jove Dasatinib (BMS-354825) inhibits Stat5 signaling associated with apoptosis in chronic myelogenous leukemia cells Mol. Cancer Ther., April 1, 2007; 6(4): 1400 - 1405. [Abstract] [Full Text] [PDF]
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A. Hochhaus, H. M. Kantarjian, M. Baccarani, J. H. Lipton, J. F. Apperley, B. J. Druker, T. Facon, S. L. Goldberg, F. Cervantes, D. Niederwieser, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy Blood, March 15, 2007; 109(6): 2303 - 2309. [Abstract] [Full Text] [PDF]
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S. Soverini, S. Colarossi, A. Gnani, F. Castagnetti, G. Rosti, C. Bosi, S. Paolini, M. Rondoni, P. P. Piccaluga, F. Palandri, et al. Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain Haematologica, March 1, 2007; 92(3): 401 - 404. [Abstract] [Full Text] [PDF]
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E. Weisberg, L. Catley, R. D. Wright, D. Moreno, L. Banerji, A. Ray, P. W. Manley, J. Mestan, D. Fabbro, J. Jiang, et al. Beneficial effects of combining nilotinib and imatinib in preclinical models of BCR-ABL+ leukemias Blood, March 1, 2007; 109(5): 2112 - 2120. [Abstract] [Full Text] [PDF]
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H. M. Kantarjian, F. Giles, A. Quintas-Cardama, and J. Cortes Important Therapeutic Targets in Chronic Myelogenous Leukemia Clin. Cancer Res., February 15, 2007; 13(4): 1089 - 1097. [Abstract] [Full Text] [PDF]
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A. Quintas-Cardama, H. Kantarjian, D. Jones, C. Nicaise, S. O'Brien, F. Giles, M. Talpaz, and J. Cortes Dasatinib (BMS-354825) is active in Philadelphia chromosome-positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure Blood, January 15, 2007; 109(2): 497 - 499. [Abstract] [Full Text] [PDF]
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S. Branford Chronic Myeloid Leukemia: Molecular Monitoring in Clinical Practice Hematology, January 1, 2007; 2007(1): 376 - 383. [Abstract] [Full Text] [PDF]
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D. A. Thomas Philadelphia Chromosome Positive Acute Lymphocytic Leukemia: A New Era of Challenges Hematology, January 1, 2007; 2007(1): 435 - 443. [Abstract] [Full Text] [PDF]
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F. R. Luo, Z. Yang, A. Camuso, R. Smykla, K. McGlinchey, K. Fager, C. Flefleh, S. Castaneda, I. Inigo, D. Kan, et al. Dasatinib (BMS-354825) Pharmacokinetics and Pharmacodynamic Biomarkers in Animal Models Predict Optimal Clinical Exposure Clin. Cancer Res., December 1, 2006; 12(23): 7180 - 7186. [Abstract] [Full Text] [PDF]
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S. Soverini, G. Martinelli, S. Colarossi, A. Gnani, F. Castagnetti, G. Rosti, C. Bosi, S. Paolini, M. Rondoni, P. P. Piccaluga, et al. Presence or the Emergence of a F317L BCR-ABL Mutation May Be Associated With Resistance to Dasatinib in Philadelphia Chromosome Positive Leukemia J. Clin. Oncol., November 20, 2006; 24(33): e51 - e52. [Full Text] [PDF]
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W. Fiskus, M. Pranpat, M. Balasis, P. Bali, V. Estrella, S. Kumaraswamy, R. Rao, K. Rocha, B. Herger, F. Lee, et al. Cotreatment with Vorinostat (Suberoylanilide Hydroxamic Acid) Enhances Activity of Dasatinib (BMS-354825) against Imatinib Mesylate-Sensitive or Imatinib Mesylate-Resistant Chronic Myelogenous Leukemia Cells. Clin. Cancer Res., October 1, 2006; 12(19): 5869 - 5878. [Abstract] [Full Text] [PDF]
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H. A. Bradeen, C. A. Eide, T. O'Hare, K. J. Johnson, S. G. Willis, F. Y. Lee, B. J. Druker, and M. W. Deininger Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)-based mutagenesis screen: high efficacy of drug combinations Blood, October 1, 2006; 108(7): 2332 - 2338. [Abstract] [Full Text] [PDF]
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M. Baccarani, G. Saglio, J. Goldman, A. Hochhaus, B. Simonsson, F. Appelbaum, J. Apperley, F. Cervantes, J. Cortes, M. Deininger, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet Blood, September 15, 2006; 108(6): 1809 - 1820. [Abstract] [Full Text] [PDF]
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E. Jabbour, J. Cortes, H. M. Kantarjian, S. Giralt, D. Jones, R. Jones, F. Giles, B. S. Andersson, R. Champlin, and M. de Lima Allogeneic stem cell transplantation for patients with chronic myeloid leukemia and acute lymphocytic leukemia after Bcr-Abl kinase mutation-related imatinib failure Blood, August 15, 2006; 108(4): 1421 - 1423. [Abstract] [Full Text] [PDF]
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N. von Bubnoff, P. W. Manley, J. Mestan, J. Sanger, C. Peschel, and J. Duyster Bcr-Abl resistance screening predicts a limited spectrum of point mutations to be associated with clinical resistance to the Abl kinase inhibitor nilotinib (AMN107) Blood, August 15, 2006; 108(4): 1328 - 1333. [Abstract] [Full Text] [PDF]
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G. Ferrari-Amorotti, K. Keeshan, M. Zattoni, C. Guerzoni, G. Iotti, S. Cattelani, N. J. Donato, and B. Calabretta Leukemogenesis induced by wild-type and STI571-resistant BCR/ABL is potently suppressed by C/EBP{alpha} Blood, August 15, 2006; 108(4): 1353 - 1362. [Abstract] [Full Text] [PDF]
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W. Fiskus, M. Pranpat, P. Bali, M. Balasis, S. Kumaraswamy, S. Boyapalle, K. Rocha, J. Wu, F. Giles, P. W. Manley, et al. Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against Bcr-Abl-expressing human leukemia cells Blood, July 15, 2006; 108(2): 645 - 652. [Abstract] [Full Text] [PDF]
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D. L. White, V. A. Saunders, P. Dang, J. Engler, A. C. W. Zannettino, A. C. Cambareri, S. R. Quinn, P. W. Manley, and T. P. Hughes OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib Blood, July 15, 2006; 108(2): 697 - 704. [Abstract] [Full Text] [PDF]
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A. Quintas-Cardama and J. E. Cortes Chronic Myeloid Leukemia: Diagnosis and Treatment Mayo Clin. Proc., July 1, 2006; 81(7): 973 - 988. [Abstract] [Full Text] [PDF]
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N. P. Shah, F. Y. Lee, R. Luo, Y. Jiang, M. Donker, and C. Akin Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis Blood, July 1, 2006; 108(1): 286 - 291. [Abstract] [Full Text] [PDF]
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M. Talpaz, N. P. Shah, H. Kantarjian, N. Donato, J. Nicoll, R. Paquette, J. Cortes, S. O'Brien, C. Nicaise, E. Bleickardt, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N. Engl. J. Med., June 15, 2006; 354(24): 2531 - 2541. [Abstract] [Full Text] [PDF]
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H. Kantarjian, F. Giles, L. Wunderle, K. Bhalla, S. O'Brien, B. Wassmann, C. Tanaka, P. Manley, P. Rae, W. Mietlowski, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N. Engl. J. Med., June 15, 2006; 354(24): 2542 - 2551. [Abstract] [Full Text] [PDF]
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E. Abruzzese, G. Del Poeta, R. Barbato, S. Fratoni, M. M. Trawinska, D. Zangrilli, A. M. Coletta, I. M. Patroi, F. Francesconi, G. Santeusanio, et al. Complete regression of cutaneous lesions of refractory Ph+ ALL after 4 weeks of treatment with BMS-354825. Blood, June 1, 2006; 107(11): 4571 - 4572. [Full Text] [PDF]
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Z. Chen, F. Y. Lee, K. N. Bhalla, and J. Wu Potent Inhibition of Platelet-Derived Growth Factor-Induced Responses in Vascular Smooth Muscle Cells by BMS-354825 (Dasatinib) Mol. Pharmacol., May 1, 2006; 69(5): 1527 - 1533. [Abstract] [Full Text] [PDF]
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Z. Zhang and K. E. Meier New Assignments for Multitasking Signal Transduction Inhibitors Mol. Pharmacol., May 1, 2006; 69(5): 1510 - 1512. [Abstract] [Full Text] [PDF]
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M. J. Mauro and R. T. Maziarz Stem Cell Transplantation in Patients With Chronic Myelogenous Leukemia: When Should It Be Used? Mayo Clin. Proc., March 1, 2006; 81(3): 404 - 416. [Abstract] [Full Text] [PDF]
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M. J. Mauro Defining and Managing Imatinib Resistance Hematology, January 1, 2006; 2006(1): 219 - 225. [Abstract] [Full Text] [PDF]
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S. Kimura, H. Naito, H. Segawa, J. Kuroda, T. Yuasa, K. Sato, A. Yokota, Y. Kamitsuji, E. Kawata, E. Ashihara, et al. NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia Blood, December 1, 2005; 106(12): 3948 - 3954. [Abstract] [Full Text] [PDF]
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M. Copland, A. Hamilton, J. W. Baird, M. Barow, E. K. Allan, L. J. Elrick, and T. L. Holyoake Dasatinib (BMS-354825) Has Increased Activity Against Bcr-Abl Compared to Imatinib in Primary CML Cells In Vitro, but Does Not Eradicate Quiescent CML Stem Cells. Blood (ASH Annual Meeting Abstracts), November 16, 2005; 106(11): 695 - 695. [Abstract]
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F. Y. Lee, M.-L. Wen, R. Bhide, A. Camuso, S. Castenada, K. Fager, C. Flefleh, I. Inigo, D. Kan, R. Luo, et al. Dasatinib (BMS-354825) Overcomes Multiple Mechanisms of Imatinib Resistance in Chronic Myeloid Leukemia (CML). Blood (ASH Annual Meeting Abstracts), November 16, 2005; 106(11): 1994 - 1994. [Abstract]
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C. Peng, Y. Hu, F. Y. Lee, and S. Li Targeting Chronic Myeloid Leukemia (CML) Stem Cells by BMS-214662 in Mice. Blood (ASH Annual Meeting Abstracts), November 16, 2005; 106(11): 2861 - 2861. [Abstract]
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N. P. Shah Loss of Response to Imatinib: Mechanisms and Management Hematology, January 1, 2005; 2005(1): 183 - 187. [Abstract] [Full Text] [PDF]
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R. L. Ilaria Jr. Pathobiology of Lymphoid and Myeloid Blast Crisis and Management Issues Hematology, January 1, 2005; 2005(1): 188 - 194. [Abstract] [Full Text] [PDF]
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