| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Experimental Therapeutics, Molecular Targets, and Chemical Biology |
1 Department of Medicine, Division of Hematology/Oncology, Oregon Health and Science University; 2 Portland Veterans Affairs Medical Center, Portland, Oregon; 3 Oncology Drug Discovery, Bristol-Myers Squibb, Princeton, New Jersey; 4 Department of Medicine, University Medical Center Eppendorf, Hamburg, Germany; and 5 Howard Hughes Medical Institute, Chevy Chase, Maryland
Requests for reprints: Michael C. Heinrich, Portland Veterans Affairs Medical Center, R&D-19, 3710 Southwest U.S. Veterans Hospital Road, Portland, OR 97239. Phone: 503-220-3405; Fax: 503-402-2817; E-mail: heinrich{at}ohsu.edu.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Imatinib mesylate is a potent KIT tyrosine kinase inhibitor (11) and is now the standard frontline therapy for advanced GISTs (2, 12). Although imatinib is a potent inhibitor of the kinase activity of wild-type (WT) KIT and GIST-associated juxtamembrane domain mutant KIT isoforms, most KIT activation loop mutations are resistant to clinically achievable doses of imatinib (2, 11–16). Imatinib only binds to the inactive conformation of KIT; however, KIT activation loop mutations not only activate kinase activity but also stabilize the activation loop in a conformation that does not allow productive imatinib binding (10, 17, 18). Activating KIT activation loop mutations are found in association with acute myelogenous leukemia (AML; ref. 5), mast cell disease (in particular systemic mastocytosis; refs. 4, 13), a subset of sinonasal natural killer/T-cell non-Hodgkin lymphoma (6, 7), seminoma/dysgerminoma (8, 9), and imatinib-resistant GIST (2, 12).
Dasatinib, formerly known as BMS-354825, is an ATP-competitive, dual SRC/ABL inhibitor (19). Notably, dasatinib can inhibit BCR-ABL activation loop mutations that are found in some chronic myelogenous leukemia (CML) patients with acquired clinical resistance to imatinib (20). Some small-molecule SRC/ABL inhibitors also have potency against KIT kinase (11, 14, 21, 22). Therefore, we hypothesized that dasatinib might inhibit the kinase activity of both WT and mutant KIT isoforms.
We report herein that dasatinib potently inhibits WT KIT and juxtamembrane domain mutant KIT autophosphorylation and KIT-dependent activation of downstream pathways important for cell viability and cell survival, such as Ras/mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase/Akt, and Janus-activated kinase/signal transducers and activators of transcription (STAT). Furthermore, we show that dasatinib is a potent inhibitor of imatinib-resistant KIT activation loop mutants and induces apoptosis in mast cell and leukemic cell lines expressing these mutations.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Site-directed mutagenesis and generation of a Ba/F3 cell line expressing mutant KIT. KIT cDNA was generously provided by Dr. Axel Ullrich (Department of Molecular Biology, Max Planck Institute for Biochemistry, Martinsried, Munich, Germany) and cloned into the pLXSN retroviral vector plasmid (BD Biosciences, Palo Alto, CA), the pCDNA3.1 vector plasmid, or the M5gNeo plasmid (26). Site-directed mutagenesis was used to create the D816V, D816Y, D816F mutations (QuickChange kit, Stratagene, La Jolla, CA) and all mutations were confirmed by bidirectional sequencing (27). Retroviral transduction was done and Ba/F3 cell lines stably expressing mutant KIT isoforms were generated by double selection for G418 resistance and IL-3-independent growth (28–30).
Transient transfections of CHO-K1 Chinese hamster cell lines with KIT WT or mutant isoforms were done using a lipofection assay (LipofectAMINE kit purchased from Life Technologies-Invitrogen). Cells were treated with dasatinib 24 hours after transfection (2).
Antibodies and reagents. An anti-KIT rabbit polyclonal antibody, an anti-STAT3 mouse monoclonal antibody (both Santa Cruz Biotechnology, Santa Cruz, CA), an anti-AKT (polyclonal) rabbit antibody (Cell Signaling Technology, Beverly MA), and an anti-MAPK1/2 [extracellular signal-regulated kinase 1/2 (ERK1/2)] rabbit monoclonal antibody (Upstate Biotechnology, Lake Placid, NY) were used at a 1:5,000 to 1:1,000 dilution. Antiphosphotyrosine KIT antibodies (Tyr568/570 and Tyr703), an antiphosphothreonine/tyrosine MAPK (Thr202/Tyr204) antibody, an antiphosphothreonine (Thr308) and an antiphosphoserine (Ser473) AKT antibody, an antiphosphotyrosine (Tyr705) STAT3 antibody, and a pan-antiphosphotyrosine antibody (clone PY20) were used at dilutions of 1:100 to 1:2,000 (all from Cell Signaling Technology). Peroxidase-conjugated goat anti-mouse antibody and goat anti-rabbit antibody were used at 1:5,000 and 1:10,000 dilutions, respectively (Bio-Rad, Hercules, CA). Protein A/G PLUS-Agarose immunoprecipitation reagent was purchased from Santa Cruz Biotechnology. The small-molecule compound dasatinib (formerly BMS-354825) was obtained from Bristol-Myers Squibb (Princeton, NJ). Imatinib mesylate (STI571/Gleevec) was purchased from the Oregon Health Science University Hospital pharmacy (Portland, OR). Imatinib and dasatinib were dissolved in DMSO to create 10 mmol/L stock solutions and stored at –20°C.
Western blots. Cells (
5 x 107) were exposed to varying concentrations of dasatinib and cultured for 90 minutes at 37°C in a 5% CO2 atmosphere. Cell pellets were lysed with 100 to 150 µL of protein lysis buffer (50 mmol/L Tris, 150 mmol/L NaCl, 1% NP40, 0.25% deoxycholate with added inhibitors aprotinin, AEBSF, leupeptin, pepstatin, sodium orthovanadate, and sodium pyruvate). Protein from cell lysates (500-2,000 µg) was used for immunoprecipitation experiments and 75 to 200 µg protein from cell lysates were used for whole cell protein analysis by Western immunoblot assays as previously described (28).
Proliferation assays. Cells were added to 96-well plates at densities 30,000 cells per well. Dasatinib was added and proliferation was measured at 72 hours using an 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt (XTT)–based assay (Roche Molecular Biochemicals, Indianapolis, IN; ref. 11).
Apoptosis assays. Cells were incubated with dasatinib for 48 to 72 hours and translocation of phosphatidylserine from the inner to the outer leaflet of the plasma membrane as an early indicator of apoptosis was analyzed using an Annexin V-FITC kit (Immunotech, Marseilles, France) and a FACScalibur flow cytometer loaded with CellQuest analysis software (BD, Heidelberg, Germany; ref. 11).
Data analysis. Dose-effect plots were created to calculate the IC50 for the treatment effect of dasatinib for each cell line (Calcusyn Software available from Biosoft, Cambridge, United Kingdom; ref. 29).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
10 nmol/L, which is nearly identical to the previously reported results for imatinib (Fig. 2A; refs. 11, 16). Imatinib potently inhibited cellular proliferation and induced apoptosis of this cell line in the low nanomolar range (Fig. 2; ref. 11). Therefore, we tested whether dasatinib had similar biological effects. Both dasatinib and imatinib inhibited cellular proliferation of HMC-1.1 cells with an IC50 of 5 to 10 nmol/L (Fig. 2B). As shown in Fig. 2C, dasatinib induced apoptosis of HMC-1.1 cells with an IC50 of 14 nmol/L, whereas the IC50 for imatinib was 70 nmol/L. These data indicate that in HMC-1.1 cells, KIT kinase activation is required for cellular proliferation and survival and dasatinib is at least as potent as imatinib for inhibiting the KIT V560G juxtamembrane domain mutation.
|
|
We tested the activity of dasatinib against the spontaneously occurring murine mastocytosis cell line, p815, which expresses a murine KIT D814Y mutation that is homologous to the human D816Y mutation. Dasatinib potently inhibited KIT autophosphorylation with an IC50 of 1 to 10 nmol/L and inhibited the cellular proliferation and induced apoptosis of p815 cells with IC50 values of 10 to 25 and 25 nmol/L, respectively (Fig. 3D-F). Therefore, unlike our results with the HMC-1.2 cells, dasatinib inhibition of KIT kinase in p815 cells was strongly correlated with inhibition of cellular proliferation and induction of apoptosis. Notably, high-dose imatinib (>1,000 nmol/L) inhibited KIT autophosphorylation. A dose of 1,200 nmol/L imatinib inhibited the proliferation of p815 cells by 30% but did not significantly induce programmed cell death.
Effects of different amino acid substitutions of KIT aspartic acid 816 (D816) on sensitivity to dasatinib. Our results with the HMC-1.2 and p815 cell lines suggested that dasatinib might have different potency against D816Y than against D816V mutations. Alternatively, these results could reflect differences in activity of dasatinib against human or murine KIT and/or differences in drug uptake by the different cell lines. To address this issue, we generated isogenic factor–independent Ba/F3 cell lines expressing systemic mastocytosis–associated codon 816 mutations with an interchange of aspartic acid to valine (D816V), tyrosine (D816Y), or phenylalanine (D816F). Dasatinib inhibited the autophosphorylation of human KIT D816V and D816F with an IC50 of 100 nmol/L. However, the IC50 for inhibition of autophosphorylation of the KIT D816Y mutation was significantly lower (IC50 1-10 nmol/L; Fig. 4A).
|
Dasatinib is 1 log more potent against WT or juxtamembrane domain mutant KIT isoforms than activation loop mutant KIT isoforms. Our results suggested that dasatinib was less active against KIT activation loop mutant isoforms than against WT or juxtamembrane domain mutant KIT. However, we were unable to directly compare this in our isogenic Ba/F3 system, as we could not establish an IL-3-independent cell line expressing WT or juxtamembrane domain mutant KIT. Thus, we could not directly compare WT KIT to activation loop mutant KIT in the same cellular context. Therefore, we did additional experiments in which we transiently transfected CHO-K1 cells with expression vectors encoding WT or mutant KIT isoforms. Transfected cells were treated with dasatinib and biochemically analyzed as described above. Consistent with our previous results, dasatinib inhibited the autophosphorylation of SCF-stimulated WT KIT (analogous to M-07eE) or juxtamembrane domain mutant KIT (analogous to the mutation in HMC-1.1) with an IC50 of 1 to 10 nmol/L, whereas the IC50 for inhibition of autophosphorylation of the KIT D816V and D816H mutations [reported in <5% of systemic mastocytosis (33) and 7% of seminoma cases (8)] was 100 to 500 nmol/L (Fig. 4C). Some lane-to-lane variation in total KIT expression is apparent in Fig. 4; such differences are partially attributable to variations in efficiency of immunoprecipitation between experimental conditions and also to the previously described inverse association between kinase activation and protein degradation (i.e., KIT turnover is increased when the kinase is activated; ref. 34).
Dasatinib inhibits KIT-dependent activation of downstream signaling pathways. We studied the effects of inhibition of KIT kinase by dasatinib on the activation status of KIT-dependent downstream signaling pathways, including MAPK, AKT, and STAT3. Figure 5 shows representative Western blots for factor-independent Ba/F3 cells expressing human KIT D816V, D816F, or D816Y mutations. For comparison, we also analyzed the effects of dasatinib of activation of MAPK1/2, AKT, and STAT3 in HMC-1.1, HMC-1.2, and p815 cells. MAPK1/2 (ERK1/2), STAT3, and AKT are constitutively activated in these cells. The phosphorylation of STAT3 and MAPK1 was potently and completely inhibited in dasatinib-treated BaF3 D816V/Y/F cells with IC50 values that were similar to those required for inhibition of KIT autophosphorylation. STAT3 activation was potently but incompletely inhibited in dasatinib-treated p815 and HMC-1.2 cells. In contrast to the other cell lines, STAT3 activation was only minimally inhibited in dasatinib-treated HMC-1.1 cells. AKT activation was potently but incompletely inhibited in all tested cell lines using dasatinib doses of 10 to 1,000 nmol/L. Similarly, MAPK2 activation was also less potently inhibited than MAPK1 (Fig. 5). Notably, dasatinib-induced inhibition of proliferation and induction of apoptosis are strongly correlated with inhibiting the activation of KIT, MAPK (MAPK1 > MAPK2), and AKT. In contrast, STAT3 activation does not correlate with cellular proliferation and/or avoidance of apoptosis.
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Gain-of-function point mutations of the KIT activation loop are associated with certain human neoplasms, including systemic mast cell disorders (13, 33), AML (5), seminoma/dysgerminoma (8, 39), and GIST (both primary and imatinib-resistant GIST; refs. 12, 40). In the case of mast cell disorders, seminoma, and AML, the most frequent KIT mutation is the replacement of the normal aspartic acid residue at codon 816 of the activation loop with a valine residue (D816V). The D816V mutation results in constitutive activation of KIT kinase activity and is predicted to help stabilize the activation loop in the active conformation. In addition to D816V, other mutations involving codon 816 have been reported in systemic mast cell disorders (D816Y and D816F; refs. 13, 33), AML (D816Y; refs. 5, 41), and/or seminomas (D816Y and D816H; refs. 8, 9, 42). Consistent with the structural model of imatinib binding to KIT, the kinase activity of all of these mutants is resistant to imatinib (2, 8, 13).
Based on previous reports of the activity of some small-molecule compounds against KIT activation loop mutations (21, 43) and specifically, of some SRC and/or ABL inhibitors against KIT (19), we hypothesized that dasatinib might also inhibit the kinase activity of KIT. In our studies, we found dasatinib to be a potent inhibitor of WT KIT with an IC50 for inhibition of autophosphorylation and cellular proliferation of 5 to 10 nmol/L. In comparison, the IC50 for inhibition of autophosphorylation and proliferation in these same cells by imatinib was 10- to 20-fold higher (100 nmol/L; ref. 11). The IC50 for dasatinib inhibition of KIT autophosphorylation that we obtained using cell-based assays of full-length KIT is very similar to that reported by Lombardo et al. (19) using cell-free assays of kinase domain–only recombinant KIT enzyme.
Juxtamembrane domain mutations of KIT are commonly associated with human GISTs (summarized in ref. 12) and a minority of cases of systemic mastocytosis (33) and AML (5, 44). Dasatinib also potently inhibits KIT juxtamembrane domain mutations with an IC50 of 1 to 10 nmol/L. Notably, dasatinib had similar potency to imatinib for inhibition of KIT autophosphorylation and cellular proliferation in a mast cell line expressing juxtamembrane domain mutant KIT (HMC-1.1) and was even more potent than imatinib for inducing apoptosis of this cell line.
Dasatinib is a much more potent inhibitor of KIT activation loop mutants than imatinib, with IC50 values for inhibition of autophosphorylation of KIT D816 mutants in the range of 10 to 100 nmol/L. Interestingly, the potency of the dasatinib against KIT kinase is differentially influenced by various activation loop mutations. Notably, KIT D816Y is 10-fold more sensitive to dasatinib than KIT D816V/F. In addition, KIT D816F is 2-fold more sensitive to dasatinib compared with KIT D816V.
Our results suggest that the conformation of the KIT activation loop does influence dasatinib potency, perhaps due to secondary changes in the ATP-binding pocket that influence drug binding. Alternatively, the different activation loop mutations might have differential abilities to stabilize the activation loop in the active conformation and prevent KIT from assuming an inactive kinase conformation that has higher dasatinib-binding affinity. This hypothesis is supported by our observation that imatinib is more potent against D816Y than against D816V/F. Further structural studies are needed to explain these experimental results and to compare the dasatinib liganded structures of KIT and ABL.
In our studies, inhibition of KIT kinase in HMC-1.1 (human mastocytosis) and p815 (murine mastocytosis) resulted in inhibition of cellular proliferation and induction of apoptosis. This suggests that therapeutic inhibition of KIT kinase would be effective for human mastocytosis that is associated with KIT D816 mutations. There are other lines of evidence to support this hypothesis: (a) KIT kinase inhibition is developmentally required for mast cell formation (1, 3, 4); (b) imatinib-induced inhibition of an alternative oncogenic kinase (FIP1L1-PDGFRA) results in marked clinical responses in variant systemic mastocytosis associated with this genomic alteration (45); (c) inhibition of KIT D816V by the kinase inhibitor PKC412 resulted in hematologic and clinical improvement in a patient with mast cell leukemia (46).
It should be noted that the HMC-1.2 cell line (human mastocytosis with KIT V560G/D816V) was less sensitive to the antiproliferative effects of dasatinib. Dasatinib potently inhibited KIT in these cells but this seemed to be insufficient to inhibit cellular proliferation or induce apoptosis. We speculate that other secondary oncogenic events, which developed during the prolonged cell passaging that gave rise to this cell line, are responsible for the apparent "disconnect" between inhibiting KIT kinase and effects on cellular proliferation and survival.
Dasatinib is currently in phase I/II trials for CML. Based on the preliminary reports of these studies, it seems that this drug is safe, well tolerated, and efficacious in the setting of imatinib-resistant CML (47). The pharmacokinetic data from these trials indicate that drug levels required to inhibit KIT activation loop mutations shown in the present studies can be safely achieved in the systemic circulation of patients. Based on our studies, we predict that dasatinib would have biological and clinical activity against human diseases associated with KIT activation loop mutations, including systemic mastocytosis (33), AML (5, 44), CDDP-resistant/refractory (39), seminoma/dysgerminoma (8, 9), and imatinib-resistant GIST (12).
|
Acknowledgments |
|---|
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.
|
Footnotes |
|---|
Received 6/15/05. Revised 9/18/05. Accepted 10/26/05.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
and transforming growth factor-ß1. Blood 1999;94:2319–32.This article has been cited by other articles:
|
|
 |
|
  S. Faderl, A. Pal, W. Bornmann, M. Albitar, D. Maxwell, Q. Van, Z. Peng, D. Harris, Z. Liu, I. Hazan-Halevy, et al. Kit Inhibitor APcK110 Induces Apoptosis and Inhibits Proliferation of Acute Myeloid Leukemia Cells Cancer Res., May 1, 2009; 69(9): 3910 - 3917. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Sun, M. Pedersen, and L. Ronnstrand The D816V Mutation of c-Kit Circumvents a Requirement for Src Family Kinases in c-Kit Signal Transduction J. Biol. Chem., April 24, 2009; 284(17): 11039 - 11047. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-F. Wong Dasatinib dosing strategies in Philadelphia chromosome-positive leukemia Journal of Oncology Pharmacy Practice, March 1, 2009; 15(1): 17 - 27. [Abstract] [PDF]
|
|
|
|
 |
|
 K. He, M. W. Lago, R. A. Iyer, W.-C. Shyu, W. G. Humphreys, and L. J. Christopher Lacteal Secretion, Fetal and Maternal Tissue Distribution of Dasatinib in Rats Drug Metab. Dispos., December 1, 2008; 36(12): 2564 - 2570. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W.-Y. Kim, D. J. Chang, B. Hennessy, H. J. Kang, J. Yoo, S.-H. Han, Y.-S. Kim, H.-J. Park, S.-Y. Geo, G. Mills, et al. A Novel Derivative of the Natural Agent Deguelin for Cancer Chemoprevention and Therapy Cancer Prevention Research, December 1, 2008; 1(7): 577 - 587. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. R. Judson Prognosis, Imatinib Dose, and Benefit of Sunitinib in GIST: Knowing the Genotype J. Clin. Oncol., November 20, 2008; 26(33): 5322 - 5325. [Full Text] [PDF]
|
|
|
|
|
|
L. J. Christopher, D. Cui, W. Li, A. Barros Jr., V. K. Arora, H. Zhang, L. Wang, D. Zhang, J. A. Manning, K. He, et al. Biotransformation of [14C]Dasatinib: In Vitro Studies in Rat, Monkey, and Human and Disposition after Administration to Rats and Monkeys Drug Metab. Dispos., July 1, 2008; 36(7): 1341 - 1356. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. J. Christopher, D. Cui, C. Wu, R. Luo, J. A. Manning, S. J. Bonacorsi, M. Lago, A. Allentoff, F. Y. F. Lee, B. McCann, et al. Metabolism and Disposition of Dasatinib after Oral Administration to Humans Drug Metab. Dispos., July 1, 2008; 36(7): 1357 - 1364. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Verstovsek, A. Tefferi, J. Cortes, S. O'Brien, G. Garcia-Manero, A. Pardanani, C. Akin, S. Faderl, T. Manshouri, D. Thomas, et al. Phase II Study of Dasatinib in Philadelphia Chromosome-Negative Acute and Chronic Myeloid Diseases, Including Systemic Mastocytosis Clin. Cancer Res., June 15, 2008; 14(12): 3906 - 3915. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Heinrich, H. Joensuu, G. D. Demetri, C. L. Corless, J. Apperley, J. A. Fletcher, D. Soulieres, S. Dirnhofer, A. Harlow, A. Town, et al. Phase II, Open-Label Study Evaluating the Activity of Imatinib in Treating Life-Threatening Malignancies Known to Be Associated with Imatinib-Sensitive Tyrosine Kinases Clin. Cancer Res., May 1, 2008; 14(9): 2717 - 2725. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Mayerhofer, K. V. Gleixner, A. Hoelbl, S. Florian, G. Hoermann, K. J. Aichberger, M. Bilban, H. Esterbauer, M.-T. Krauth, W. R. Sperr, et al. Unique Effects of KIT D816V in BaF3 Cells: Induction of Cluster Formation, Histamine Synthesis, and Early Mast Cell Differentiation Antigens J. Immunol., April 15, 2008; 180(8): 5466 - 5476. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Fernandez, A. Sanguino, Z. Peng, A. Crespo, E. Ozturk, X. Zhang, S. Wang, W. Bornmann, and G. Lopez-Berestein Rational Drug Redesign to Overcome Drug Resistance in Cancer Therapy: Imatinib Moving Target Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 589 - 599. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Chou, M. E. Farkas, S. M. Tsai, D. Alvarez, P. B. Dervan, and J. M. Gottesfeld Small molecules targeting histone H4 as potential therapeutics for chronic myelogenous leukemia Mol. Cancer Ther., April 1, 2008; 7(4): 769 - 778. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Ramirez and J. F. DiPersio Therapy Options in Imatinib Failures Oncologist, April 1, 2008; 13(4): 424 - 434. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kneidinger, U. Schmidt, U. Rix, K. V. Gleixner, A. Vales, C. Baumgartner, C. Lupinek, M. Weghofer, K. L. Bennett, H. Herrmann, et al. The effects of dasatinib on IgE receptor-dependent activation and histamine release in human basophils Blood, March 15, 2008; 111(6): 3097 - 3107. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Tefferi, S. Verstovsek, and A. Pardanani How we diagnose and treat WHO-defined systemic mastocytosis in adults Haematologica, January 1, 2008; 93(1): 6 - 9. [Full Text] [PDF]
|
|
|
|
 |
|
 B. M. Jensen, M. A. Beaven, S. Iwaki, D. D. Metcalfe, and A. M. Gilfillan Concurrent Inhibition of Kit- and Fc{epsilon}RI-Mediated Signaling: Coordinated Suppression of Mast Cell Activation J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 128 - 138. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Haferlach Molecular Genetic Pathways as Therapeutic Targets in Acute Myeloid Leukemia Hematology, January 1, 2008; 2008(1): 400 - 411. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J A Schumacher, K S J Elenitoba-Johnson, and M S Lim Detection of the c-kit D816V mutation in systemic mastocytosis by allele-specific PCR J. Clin. Pathol., January 1, 2008; 61(1): 109 - 114. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Patel, A. T. Phan, and V. Kuryavyi Human telomere, oncogenic promoter and 5'-UTR G-quadruplexes: diverse higher order DNA and RNA targets for cancer therapeutics Nucleic Acids Res., December 3, 2007; 35(22): 7429 - 7455. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. V. Gleixner, M. Mayerhofer, K. Sonneck, A. Gruze, P. Samorapoompichit, C. Baumgartner, F. Y. Lee, K. J. Aichberger, P. W. Manley, D. Fabbro, et al. Synergistic growth-inhibitory effects of two tyrosine kinase inhibitors, dasatinib and PKC412, on neoplastic mast cells expressing the D816V-mutated oncogenic variant of KIT Haematologica, November 1, 2007; 92(11): 1451 - 1459. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. J.L. Kaspers and C. M. Zwaan Pediatric acute myeloid leukemia: towards high-quality cure of all patients Haematologica, November 1, 2007; 92(11): 1519 - 1532. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Fizazi The role of Src in prostate cancer Ann. Onc., November 1, 2007; 18(11): 1765 - 1773. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Voisset, S. Lopez, P. Dubreuil, and P. De Sepulveda The tyrosine kinase FES is an essential effector of KITD816V proliferation signal Blood, October 1, 2007; 110(7): 2593 - 2599. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K. Todd, S. M. Haider, G. N. Parkinson, and S. Neidle Sequence occurrence and structural uniqueness of a G-quadruplex in the human c-kit promoter Nucleic Acids Res., September 27, 2007; 35(17): 5799 - 5808. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Munugalavadla, E. C. Sims, J. Borneo, R. J. Chan, and R. Kapur Genetic and pharmacologic evidence implicating the p85{alpha}, but not p85{beta}, regulatory subunit of PI3K and Rac2 GTPase in regulating oncogenic KIT-induced transformation in acute myeloid leukemia and systemic mastocytosis Blood, September 1, 2007; 110(5): 1612 - 1620. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Guo, N. P. Agaram, G. C. Wong, G. Hom, D. D'Adamo, R. G. Maki, G. K. Schwartz, D. Veach, B. D. Clarkson, S. Singer, et al. Sorafenib Inhibits the Imatinib-Resistant KITT670I Gatekeeper Mutation in Gastrointestinal Stromal Tumor Clin. Cancer Res., August 15, 2007; 13(16): 4874 - 4881. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. F. Peterson, A. Boyapati, E.-Y. Ahn, J. R. Biggs, A. J. Okumura, M.-C. Lo, M. Yan, and D.-E. Zhang Acute myeloid leukemia with the 8q22;21q22 translocation: secondary mutational events and alternative t(8;21) transcripts Blood, August 1, 2007; 110(3): 799 - 805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Kondo, K. V. Gleixner, M. Mayerhofer, A. Vales, A. Gruze, P. Samorapoompichit, K. Greish, M.-T. Krauth, K. J. Aichberger, W. F. Pickl, et al. Identification of heat shock protein 32 (Hsp32) as a novel survival factor and therapeutic target in neoplastic mast cells Blood, July 15, 2007; 110(2): 661 - 669. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Grabellus, P. Ebeling, K. Worm, S.-Y. Sheu, G. Antoch, A. Frilling, and K. W Schmid Double resistance to imatinib and AMG 706 caused by multiple acquired KIT exon 17 mutations in a gastrointestinal stromal tumour Gut, July 1, 2007; 56(7): 1025 - 1026. [Full Text] [PDF]
|
|
|
|
|
|
T. Guida, S. Anaganti, L. Provitera, R. Gedrich, E. Sullivan, S. M. Wilhelm, M. Santoro, and F. Carlomagno Sorafenib Inhibits Imatinib-Resistant KIT and Platelet-Derived Growth Factor Receptor {beta} Gatekeeper Mutants Clin. Cancer Res., June 1, 2007; 13(11): 3363 - 3369. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Fernandez, A. Sanguino, Z. Peng, A. Crespo, E. Ozturk, X. Zhang, S. Wang, W. Bornmann, and G. Lopez-Berestein Rational Drug Redesign to Overcome Drug Resistance in Cancer Therapy: Imatinib Moving Target Cancer Res., May 1, 2007; 67(9): 4028 - 4033. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Shor, E. A. Keschman, F. Y. Lee, C. Muro-Cacho, G. D. Letson, J. C. Trent, W. J. Pledger, and R. Jove Dasatinib Inhibits Migration and Invasion in Diverse Human Sarcoma Cell Lines and Induces Apoptosis in Bone Sarcoma Cells Dependent on Src Kinase for Survival Cancer Res., March 15, 2007; 67(6): 2800 - 2808. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Puttini, A. M. L. Coluccia, F. Boschelli, L. Cleris, E. Marchesi, A. Donella-Deana, S. Ahmed, S. Redaelli, R. Piazza, V. Magistroni, et al. In vitro and In vivo Activity of SKI-606, a Novel Src-Abl Inhibitor, against Imatinib-Resistant Bcr-Abl+ Neoplastic Cells Cancer Res., December 1, 2006; 66(23): 11314 - 11322. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. L. Corless, P. Harrell, M. Lacouture, T. Bainbridge, C. Le, K. Gatter, C. White Jr, S. Granter, and M. C. Heinrich Allele-Specific Polymerase Chain Reaction for the Imatinib-Resistant KIT D816V and D816F Mutations in Mastocytosis and Acute Myelogenous Leukemia J. Mol. Diagn., November 1, 2006; 8(5): 604 - 612. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Paschka, G. Marcucci, A. S. Ruppert, K. Mrozek, H. Chen, R. A. Kittles, T. Vukosavljevic, D. Perrotti, J. W. Vardiman, A. J. Carroll, et al. Adverse Prognostic Significance of KIT Mutations in Adult Acute Myeloid Leukemia With inv(16) and t(8;21): A Cancer and Leukemia Group B Study J. Clin. Oncol., August 20, 2006; 24(24): 3904 - 3911. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Gabillot-Carre, Y. Lepelletier, M. Humbert, P. de Sepuvelda, N. B. Hamouda, J. P. Zappulla, R. Liblau, A. Ribadeau-Dumas, F. Machavoine, S. Letard, et al. Rapamycin inhibits growth and survival of D816V-mutated c-kit mast cells Blood, August 1, 2006; 108(3): 1065 - 1072. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Tokarski, J. A. Newitt, C. Y. J. Chang, J. D. Cheng, M. Wittekind, S. E. Kiefer, K. Kish, F. Y.F. Lee, R. Borzillerri, L. J. Lombardo, et al. The Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain Elucidates Its Inhibitory Activity against Imatinib-Resistant ABL Mutants Cancer Res., June 1, 2006; 66(11): 5790 - 5797. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
