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Action of the Src Family Kinase Inhibitor, Dasatinib (BMS-354825), on Human Prostate Cancer Cells

¹ Molecular Oncology and ² Biostatistics Programs, H. Lee Moffitt Cancer Center and Research Institute, ³ Department of Pathology, University of South Florida College of Medicine, Tampa, Florida; and ⁴ Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey

Requests for reprints: Richard Jove, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Rd, Duarte, CA 91010. Phone: 626-256-4673; Fax: 626-256-8708; E-mail: rjove{at}coh.org.

	Abstract

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Src family kinases (SFK) are currently being investigated as targets for treatment strategies in various cancers. The novel SFK/Abl inhibitor, dasatinib (BMS-354825), is a promising therapeutic agent with oral bioavailability. Dasatinib has been shown to inhibit growth of Bcr-Abl–dependent chronic myeloid leukemia xenografts in nude mice. Dasatinib also has been shown to have activity against cultured human prostate and breast cancer cells. However, the molecular mechanism by which dasatinib acts on epithelial tumor cells remains unknown. In this study, we show that dasatinib blocks the kinase activities of the SFKs, Lyn and Src, in human prostate cancer cells at low nanomolar concentrations. Moreover, focal adhesion kinase and Crk-associated substrate (p130^CAS) signaling downstream of SFKs are also inhibited at similar concentrations of dasatinib. Consistent with inhibition of these signaling pathways, dasatinib suppresses cell adhesion, migration, and invasion of prostate cancer cells at low nanomolar concentrations. Therefore, dasatinib has potential as a therapeutic agent for metastatic prostate cancers harboring activated SFK and focal adhesion kinase signaling.

	Introduction

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Elevated levels and activities of Src family kinases (SFK), including Src and Lyn, have been shown in numerous human cancer cell lines and tumor tissues (1–3). SFKs phosphorylate tyrosyl residues of critical cellular substrates, resulting in the activation of oncogenic signal transduction pathways (4, 5). One such substrate of SFKs, focal adhesion kinase (FAK), has an important role in integrin signaling (6) and is highly expressed in many tumor cells including prostate cancer (7, 8). Tyrosyl phosphorylation of FAK stimulates its ability to modulate cell adhesion, migration, and invasion (6). In addition, tyrosyl phosphorylation of Crk-associated substrate (p130^CAS), another substrate of SFKs, is important for cell motility and invasion (9, 10). Originally, dasatinib (BMS-354825) compound [N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide] was selected as a synthetic small-molecule inhibitor of SFKs (11). In addition, dasatinib was subsequently found to be a Bcr-Abl kinase inhibitor, as has been shown earlier for other SFK inhibitors (12, 13). Furthermore, a recent phase I clinical trial determined that dasatinib is a promising agent for treatment of chronic myelogenous leukemia with activated Bcr-Abl kinase. Dasatinib also showed activity against epithelial tumor cells, including human prostate and breast cancer cells (11). However, the molecular mechanisms of dasatinib's action on epithelial tumor cells remain unknown. Here, we report that dasatinib inhibits SFK/FAK/p130^CAS signaling at low nanomolar concentrations, associated with inhibition of cell adhesion, migration, and invasion of human prostate cancer cells.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Cells and reagents. DU-145 and LNCaP prostate cancer cells were obtained from American Type Culture Collection and cultured in RPMI 1640 containing 10% fetal bovine serum. Polyclonal antibodies to the phosphoproteins p-Src (Tyr416), p-FAK (Tyr576/577), p-p130^CAS (Tyr410), p-Stat3 (Tyr705), p-ERK1/2 (Thr202/Tyr204), and p-AKT (Ser473) were obtained from Cell Signaling Technologies (Cambridge, MA). Polyclonal antibodies to Lyn, FAK, and p130^CAS proteins were from Santa Cruz Biotechnology (Santa Cruz, CA). Polyclonal antibodies to the phosphoprotein p-FAK (Tyr397 and Tyr861) were from BioSource International (Camarillo, CA). Monoclonal antibody to c-Src was obtained from Upstate Biotechnology (Lake Placid, NY). Dasatinib was obtained from Bristol-Myers Squibb Pharmaceutical Research Institute (Princeton, NJ). Dasatinib was synthesized by the addition of methylpyrimidine to the 2-amino group of thiazole, followed by reaction with hydroxyethyl piperazine (11).

Lyn and Src kinase assays in vitro. Lyn and Src kinase assays were done in vitro as described in the supplier's protocol (Upstate Biotechnology). Twenty-microliter aliquots of each 25 µL reaction mixture were transferred onto the center of substrate-binding phosphocellulose paper squares. Assay squares were washed thrice with 0.75% phosphoric acid, and transferred to vials with 5 mL of scintillation cocktail. After quantifying activity with a LS6500 Scintillation Counter (Beckman Coulter, Fullerton, CA), radioactivity in assay squares was directly visualized by autoradiography.

Western blot analysis. Western blot analysis was done as previously described (14). Primary phosphospecific antibodies were incubated in TBS (pH 7.5) with 0.1% Tween 20 and 5% bovine serum albumin with gentle agitation overnight at 4°C. horseradish peroxidase–conjugated secondary antibodies were diluted in TBS or PBS with 5% nonfat milk and incubated for 1 hour at room temperature. Positive immunoreactions were detected using the Chemiluminescent Substrate system (Pierce, Rockford, IL). For immunoprecipitation of Lyn, cell lysates (300 µg) were incubated with Lyn antibody overnight at 4°C, followed by protein A/G-agarose for 1 hour at 4°C (Pierce). Samples were immunoblotted with p-Src family antibody (Tyr416), which cross-reacts with p-Lyn (Tyr396).

Cell adhesion assay. Cells (1 x 10⁵/well) were pretreated with dasatinib for 30 minutes and adhered onto fibronectin-coated 96-well plates (BD Sciences, San Jose, CA) for 1 hour at 37°C. All procedures were done as described previously (15). Briefly, nonadhered cells were removed by washing thrice with serum-free medium. Attached cells were fixed with 70% methanol for 10 minutes. Cells were stained with 0.02% crystal violet in 0.2% ethanol solution and dissolved with 100 µL Sorenson solution/well. Plates were analyzed with an automated ELISA reader at 540 nm. Each experiment was done in triplicate.

Wound healing assay for cell migration. Monolayer wounds were made using a pipette tip on confluent DU-145 cells cultured in six-well plates. Cells were treated with dasatinib or DMSO as vehicle control in a dose-dependent manner and then allowed to migrate into the denuded area for 6 hours. Cell migration was visualized at 10x magnification using a TE 2000 Inverted Fluorescence Microscope (Nikon, Melville, NY) and IPLab 3.6 software (Scanalytics, Fairfax, VA), and photographed with a Retiga 1300 CCD Camera (Qimaging, Burnaby, B.C., Canada). Distances of denuded areas were measured as pixel units.

Analysis of matrix metalloproteinase-9 activity. Matrix metalloproteinase-9 (MMP-9) activity assays were done with a MMP-9 human ELISA kit (Amersham Biosciences, Piscataway, NJ). Cells were washed with PBS twice and serum-free medium twice. Fresh serum-free medium was added to cell cultures and cells were exposed to dasatinib or DMSO as vehicle control for 24 hours. Cell culture medium was collected and concentrated using Centrifugal Ultra Filters (Millipore, Billerica, MA). Normalized proteins (2 µg/well) were added to 96-well ELISA plates. The reaction was stopped with 100 µL of 1 mol/L sulfuric acid and absorbance was measured with an automated ELISA plate reader at 450 nm. Each experiment was done in quadruplicate.

Cell invasion assay. Cell invasion assays were done on polycarbonate membrane inserts (8 um pore size; Chemicon International, Temecula, CA). DU-145 cells were washed with PBS once and serum-free medium twice. Cells were resuspended with fresh serum-free medium and dasatinib or DMSO as vehicle control was added. Cells (5 x 10⁵/well) in 300 µL of serum-free medium were placed over the inner chamber of the insert in a 24-well tissue culture plate, and 500 µL of serum-free medium was placed in the outer chamber of the insert. The plates were incubated for 24 hours at 37°C. After 24 hours, the cells that migrated through to the lower surface of the extracellular matrix layer were stained and dissolved in 10% acetic acid. Solutions were transferred to a 96-well plate and absorbances measured with an automated ELISA plate reader at 540 nm. Each experiment was done in triplicate.

Statistical analysis. Descriptive statistics, such as mean values and SD, were calculated for the biological effects of dasatinib (i.e., inhibition of cell adhesion, MMP-9 activity, and invasion) by dose levels (nmol/L). To determine statistical significance between pair-wise dose levels, the exact Wilcoxon two-sample test was used, considering the small sample sizes. One-sided tests at a significance level of 0.05 were examined. All data were analyzed using the SAS software (version 9.1, SAS Institute, Cary, NC).

	Results and Discussion

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Dasatinib inhibits Src family kinase activity in vitro and in vivo. The human DU-145 cell line is an androgen-independent, highly aggressive metastatic prostate cancer cell line, whereas the androgen-dependent human LNCaP prostate cancer cell line exhibits relatively low aggressiveness and low metastatic potential (16). A previous study reported that Lyn is expressed in a majority of primary human prostate cancers and thus might be a potential target protein for treatment of this disease (17). Dasatinib is a thiazole- and pyrimidine-based SFK/Abl kinase inhibitor (Fig. 1A). To confirm that dasatinib (BMS-354825) directly inhibits Lyn and Src kinase activity, in vitro kinase assays were done with active recombinant Lyn or Src proteins. Dasatinib showed an inhibitory effect on both Lyn and Src kinase activities with IC₅₀ values of 8.5 and 3.0 nmol/L, respectively (Fig. 1B and C).

View larger version (21K): [in this window] [in a new window]   Figure 1. Dasatinib inhibits Lyn and Src kinase activities in vitro. A, the chemical structure of dasatinib. B, for the in vitro Lyn kinase assay, 20 ng of recombinant Lyn and 0.1 mg/mL poly (Glu4-Tyr) substrate were preincubated in the presence or absence of various dasatinib concentrations for 10 minutes. [-32P]ATP (5 µCi) was added per 25 µL reaction mixture for 15 minutes. Radiolabeled reaction mixtures were transferred to substrate-binding phosphocellulose. C, for the in vitro Src kinase assay, 20 ng of recombinant Src and 250 µmol/L of synthetic Src substrate peptide were preincubated in the presence or absence of various dasatinib concentrations for 10 minutes. [-32P]ATP (10 µCi) were added per 25 µL reaction mixture for 15 minutes. Radiolabeled reaction mixtures were transferred to substrate-binding phosphocellulose. Radiolabeled substrates from both in vitro kinase assays were counted with a scintillation counter to determine IC50 values of enzyme activity and visualized by autoradiography. Points, mean; bars, ± SD (n = 3).

View larger version (28K): [in this window] [in a new window]   Figure 2. Dasatinib blocks tyrosyl phosphorylation of Lyn and Src in whole cells. A and C, DU-145 and LNCaP cells were treated with 100 nmol/L dasatinib for 6 hours. For p-Lyn detection, lysates were immunoprecipitated with Lyn antibody and blotted with p-Src family antibody (Tyr416), which cross-reacts with autophosphorylated p-Lyn (Tyr396). Western blot analysis was also done with specific antibodies to p-Src and Src. B and D, DU-145 cells were treated with 100 nmol/L dasatinib in a time-dependent manner (top) or for 6 hours in a dose-dependent manner (bottom). Western blot analysis was done as described above. DMSO was used as vehicle control for all experiments.

View larger version (38K): [in this window] [in a new window]   Figure 3. Effects of dasatinib on phosphorylation of signaling proteins downstream of SFKs. A, dasatinib blocks tyrosyl phosphorylation of FAK, but does not affect levels of total FAK in cells. DU-145 and LNCaP cells were treated with 100 nmol/L dasatinib for 6 hours. B, dasatinib decreases cell-to-cell contacts. DU-145 and LNCaP cells were treated with 100 nmol/L dasatinib for 24 hours. Decrease of cell-to-cell contact was visualized at 10x magnification by light microscopy. C, dasatinib blocks tyrosyl phosphorylation of FAK at Y576/577 and Y861, but not at Y397. DU-145 cells were treated with 100 nmol/L dasatinib in a time-dependent manner (top) or for 6 hours in a dose-dependent manner (bottom). Cell-free extracts were immunoblotted with specific antibodies to p-FAK at Tyr397, Tyr576/577, and Tyr861, and total FAK. D, dasatinib does not block phosphorylation of Stat3, ERK1/2, and AKT in cells. DU-145 cells were treated with dasatinib for 6 hours in a dose-dependent manner. Cell-free extracts were immunoblotted with specific antibodies to p-Stat3, p-ERK1/2, and p-AKT. E, dasatinib blocks tyrosyl phosphorylation of p130CAS, but does not affect levels of total p130CAS. DU-145 cells were treated with 100 nmol/L dasatinib in a time-dependent manner (top) or for 6 hours in a dose-dependent manner (bottom). Cell-free extracts were immunoblotted with specific antibody to p-p130CAS (Tyr410) and p130CAS.

Next, we examined whether dasatinib could reduce the phosphorylation levels of proteins involved in other tyrosine kinase signaling pathways. Levels of p-Stat3, p-Erk1/2, and p-Akt were not altered with dasatinib treatment (Fig. 3D). Notably, dasatinib does not induce apoptosis in DU-145 cells (data not shown), consistent with the lack of effect on levels of p-Akt and p-Stat3, both signaling proteins that are involved in tumor cell survival (18). Thus, our observations suggest that dasatinib predominantly acts by inhibiting SFK/FAK signaling in prostate cancer cells.

The p130^CAS protein is involved in integrin-mediated cell signaling and its SH3 domain interacts with FAK to form a FAK-p130 complex (6, 9). Tyrosyl phosphorylation of FAK at Tyr861 regulates its interaction with p130^CAS (19) and tyrosyl phosphorylation of p130^CAS is involved in cell motility and invasion (9, 10, 20). To determine whether inhibition of SFKs by dasatinib reduces levels of p-p130^CAS, DU-145 cells were exposed to dasatinib for time course and dose-dependent studies. Consistent with the inhibition of p-FAK levels (Fig. 3C), dasatinib decreased p-p130^CAS levels, whereas total levels of p130^CAS were unaltered (Fig. 3E). The observed reduction of p-p130^CAS levels also correlates well with the reduction of p-Lyn and p-Src levels (Fig. 2B and D).

Dasatinib inhibits cell adhesion, migration, and invasion. FAK has an important role in the integrin signaling cascade (6). Cellular adhesion to extracellular matrix proteins such as fibronectin require integrins. To assess whether dasatinib blocks cell adhesion to the extracellular matrix, DU-145 cells were pretreated with the drug for 30 minutes to inhibit levels of p-FAK and p-p130^CAS. Cell adhesion to fibronectin was significantly inhibited by 10 nmol/L of dasatinib (Fig. 4A). This finding correlates with the observed reduction of p-FAK and p-p130^CAS (Fig. 3C and E), suggesting that the effects of dasatinib on p-FAK and p-p130^CAS levels contribute to inhibition of cell adhesion to fibronectin. In addition, wound-healing assays were done to determine whether dasatinib affects cell migration. Dasatinib inhibited cell migration at 1 to 10 nmol/L after 6 hours of treatment (Fig. 4B). These findings indicate that the reduction of p-FAK and p-p130^CAS levels by dasatinib is associated with inhibition of cell adhesion and migration.

View larger version (26K): [in this window] [in a new window]   Figure 4. Dasatinib inhibits cell motility and invasion. A, dasatinib inhibits cell adhesion on fibronectin. DU-145 cells were pretreated with dasatinib for 30 minutes and adhered onto fibronectin-coated 96-well plates. Unattached cells were washed thrice with serum-free medium. Plates were read with an automated ELISA reader at 540 nm. Columns, mean; bars, ± SD; *, P = 0.028 (n = 3). B, dasatinib inhibits cell migration. Wound healing assay was done to determine whether dasatinib inhibits cell migration. After treatment with various dasatinib concentrations for 6 hours, cells were allowed to migrate into the denuded area for 6 hours. Cell migration was visualized at 10x magnification by light microscopy, and photographed with a digital camera. Width of denuded areas versus dasatinib concentration was plotted in pixels (bottom graph). C, dasatinib inhibits MMP-9 activity. DU-145 cells were washed with 1x PBS twice and serum-free medium twice. Fresh serum-free medium was added to plates and cells were exposed to dasatinib for 24 hours. Culture medium was collected and concentrated with an ultra-centrifugal filter device. Normalized proteins were added to 96-well ELISA plates. Reactions were stopped with 100 µL of 1 mol/L sulfuric acid and absorbances read with an automated ELISA plate reader at 450 nm. Columns, mean; bars, ± SD; *, P = 0.029 (n = 4). D, dasatinib inhibits cell invasion. DU145 cells in 300 µL of serum-free medium were placed over the inner chamber of the insert in a 24-well tissue culture plate, and 500 µL of serum-free medium was placed in the outer chamber of the insert. The plates were incubated for 24 hours at 37°C and 5% CO2 atmosphere. After 24 hours, the invasive cells that migrated through the lower surface of the extracellular matrix layer were stained. The stained cells were dissolved in 10% acetic acid and absorbance was read with an automated ELISA reader at 540 nm. Each experiment was done in triplicate. Columns, mean; bars, ± SD; *, P = 0.050 (n = 3).

Therapeutic implications. Dasatinib is an orally bioavailable and promising antitumor therapeutic agent for chronic myelogenous leukemia (11, 13). Recently, phase I clinical trials showed the efficacy of dasatinib for the treatment of chronic myelogenous leukemia with activated Bcr-Abl kinase.⁵ In addition, dasatinib has been advanced into clinical trials for human epithelial solid tumors.⁵ Many invasive epithelial tumors exhibit elevated SFK and FAK expression levels and activities (1–6). In this report, we show that dasatinib blocks SFK/FAK/p130^CAS signaling, resulting in inhibition of cell adhesion, migration, and invasion in prostate cancer cells. Based on this action of dasatinib on prostate cancer cells, we suggest that dasatinib has potential as an antitumor therapeutic agent in metastatic prostate cancers harboring activated SFK and FAK signaling.

	Acknowledgments

 
Grant support: NIH grants CA55652 and CA82533 (R. Jove).

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 members of our laboratory for stimulating discussions, and the Analytic Microscopy and Flow Cytometry Core Facilities at the H. Lee Moffitt Cancer Center and Research Institute. Janni Mirosevich is the recipient of Department of Defense Postdoctoral Traineeship Award W81XWH-04-1-0050.

	Footnotes

 
⁵ F. Lee et al., unpublished data.

Received 5/19/05. Revised 7/19/05. Accepted 8/ 5/05.

	References

Top Abstract Introduction Materials and Methods Results and Discussion References

 

1. Parsons SJ, Parsons JT. Src family kinases, key regulators of signal transduction. Oncogene 2004;23:7906–9.[CrossRef][Medline]
2. Summy JM, Gallick GE. Src family kinases in tumor progression and metastasis. Cancer Metastasis Rev 2003;22:337–58.[CrossRef][Medline]
3. Yeatman TJ. A renaissance for SRC. Nat Rev Cancer 2004;4:470–80.[CrossRef][Medline]
4. Bromann PA, Korkaya H, Courtneidge SA. The interplay between Src family kinases and receptor tyrosine kinases. Oncogene 2004;23:7957–68.[CrossRef][Medline]
5. Frame MC. Newest findings on the oldest oncogene; how activated src does it. J Cell Sci 2004;117:989–98.[Abstract/Free Full Text]
6. Parsons JT. Focal adhesion kinase: the first ten years. J Cell Sci 2003;116:1409–16.[Abstract/Free Full Text]
7. Playford MP, Schaller MD. The interplay between Src and integrins in normal and tumor biology. Oncogene 2004;23:7928–46.[CrossRef][Medline]
8. Slack JK, Adams RB, Rovin JD, Bissonette EA, Stoker CE, Parsons JT. Alterations in the focal adhesion kinase/Src signal transduction pathway correlate with increased migratory capacity of prostate carcinoma cells. Oncogene 2001;20:1152–63.[CrossRef][Medline]
9. Brabek J, Constancio SS, Shin NY, Pozzi A, Weaver AM, Hanks SK. CAS promotes invasiveness of Src-transformed cells. Oncogene 2004;23:7406–15.[CrossRef][Medline]
10. Shin NY, Dise RS, Schneider-Mergener J, Ritchie MD, Kilkenny DM, Hanks SK. Subsets of the major tyrosine phosphorylation sites in Crk-associated substrate (CAS) are sufficient to promote cell migration. J Biol Chem 2004;279:38331–7.[Abstract/Free Full Text]
11. Lombardo LJ, Lee FY, Chen P, et al. 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. J Med Chem 2004;47:6658–61.[CrossRef][Medline]
12. Dorsey JF, Jove R, Kraker AJ, Wu J. The pyrido[2,3-d]pyrimidine derivative PD180970 inhibits p210Bcr-Abl tyrosine kinase and induces apoptosis of K562 leukemic cells. Cancer Res 2000;60:3127–31.[Abstract/Free Full Text]
13. Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004;305:399–401.[Abstract/Free Full Text]
14. Nam S, Smith DM, Dou QP. Ester bond-containing tea polyphenols potently inhibit proteasome activity in vitro and in vivo. J Biol Chem 2001;276:13322–30.[Abstract/Free Full Text]
15. Hazlehurst LA, Damiano JS, Buyuksal I, Pledger WJ, Dalton WS. Adhesion to fibronectin via ß1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR). Oncogene 2000;19:4319–27.[CrossRef][Medline]
16. Papandreou CN, Logothetis CJ. Bortezomib as a potential treatment for prostate cancer. Cancer Res 2004;64:5036–43.[Abstract/Free Full Text]
17. Goldenberg-Furmanov M, Stein I, Pikarsky E, et al. Lyn is a target gene for prostate cancer: sequence-based inhibition induces regression of human tumor xenografts. Cancer Res 2004;64:1058–66.[Abstract/Free Full Text]
18. Yu H, Jove R. The STATs of cancer-new molecular targets come of age. Nat Rev Cancer 2004;4:97–105.[Medline]
19. Lim Y, Han I, Jeon J, Park H, Bahk YY, Oh ES. Phosphorylation of focal adhesion kinase at tyrosine 861 is crucial for Ras transformation of fibroblasts. J Biol Chem 2004;279:29060–5.[Abstract/Free Full Text]
20. Klemke RL, Leng J, Molander R, Brooks PC, Vuori K, Cheresh DA. CAS/Crk coupling serves as a "molecular switch" for induction of cell migration. J Cell Biol 1998;140:961–72.[Abstract/Free Full Text]

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				A. Serrels, I. R.J. Macpherson, T.R. J. Evans, F. Y. Lee, E. A. Clark, O. J. Sansom, G. H. Ashton, M. C. Frame, and V. G. Brunton Identification of potential biomarkers for measuring inhibition of Src kinase activity in colon cancer cells following treatment with dasatinib Mol. Cancer Ther., December 1, 2006; 5(12): 3014 - 3022. [Abstract] [Full Text] [PDF]

				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]

				L. Xin, M. A. Teitell, D. A. Lawson, A. Kwon, I. K. Mellinghoff, and O. N. Witte Progression of prostate cancer by synergy of AKT with genotropic and nongenotropic actions of the androgen receptor PNAS, May 16, 2006; 103(20): 7789 - 7794. [Abstract] [Full Text] [PDF]

				J. M. Summy and G. E. Gallick Treatment for Advanced Tumors: Src Reclaims Center Stage Clin. Cancer Res., March 1, 2006; 12(5): 1398 - 1401. [Full Text] [PDF]

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