| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Preclinical Research and Exploratory Development [A. D. L., G. L., K. G. M., J. M. C., D. B. M.], Discovery Technology [R. A. B.], and Research [M. A. B.], SUGEN, Inc., South San Francisco, California 94080
1 To whom requests for reprints should be addressed, at SUGEN, Inc., 230 East Grand Avenue, South San Francisco, CA 94080. Phone: (650) 837-3674; Fax: (650) 837-3308; E-mail: Douglas-Laird{at}sugen.com
The Src family kinases (SFKs) Src and Yes are believed to play critical roles in tumor growth, angiogenesis, invasion, and dissemination. Using a panel of highly selective and structurally diverse Src inhibitors, we found that phosphorylation of signal transducer and activator of transcription 3 [STAT3 (Y705)] and focal adhesion kinase [FAK (Y861)] was SFK dependent in cultured human colon, breast, lung, and ovarian tumor cells. These findings were reproduced in vivo in target modulation studies using tumors derived from fibroblasts overexpressing activated Src. Additionally, treatment of mice with multiple Src inhibitors resulted in inhibition of phosphorylation of FAK (Y861) and of a putative Src autophosphorylation epitope (Y419) in HT-29 human colon tumor xenografts. Next we pharmacologically examined the requirement for SFKs in asynchronous proliferation of human tumor cells. At concentrations sufficient to selectively inhibit Src, structurally diverse Src inhibitors inhibited growth of cultured human colon, breast, and lung cells on plastic under low serum conditions. In addition, these compounds inhibited anchorage-independent growth of HT-29 human colon tumor cells in soft agar. The role of SFK activity in vascular endothelial growth factor signaling was also evaluated. Inhibition of SFK signaling using structurally distinct Src inhibitors resulted in complete inhibition of vascular endothelial growth factor-dependent vascular permeability in vivo. These data demonstrate that STAT3 (Y705) and FAK (Y861) phosphoepitopes are SFK-dependent in tumor cells and reveal a requirement for SFK function in tumor cell proliferation and vascular permeability.
This article has been cited by other articles:
|
|
 |
|
  G. Giaccone and P. A. Zucali Src as a potential therapeutic target in non-small-cell lung cancer Ann. Onc., July 1, 2008; 19(7): 1219 - 1223. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
O. Potapova, A. D. Laird, M. A. Nannini, A. Barone, G. Li, K. G. Moss, J. M. Cherrington, and D. B. Mendel Contribution of individual targets to the antitumor efficacy of the multitargeted receptor tyrosine kinase inhibitor SU11248 Mol. Cancer Ther., May 1, 2006; 5(5): 1280 - 1289. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. J. Delfino, H. Stevenson, and T. E. Smithgall A Growth-suppressive Function for the c-Fes Protein-Tyrosine Kinase in Colorectal Cancer J. Biol. Chem., March 31, 2006; 281(13): 8829 - 8835. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Lin, R. Lai, L. R. Chirieac, C. Li, V. A. Thomazy, I. Grammatikakis, G. Z. Rassidakis, W. Zhang, Y. Fujio, K. Kunisada, et al. Constitutive Activation of JAK3/STAT3 in Colon Carcinoma Tumors and Cell Lines: Inhibition of JAK3/STAT3 Signaling Induces Apoptosis and Cell Cycle Arrest of Colon Carcinoma Cells Am. J. Pathol., October 1, 2005; 167(4): 969 - 980. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. M. Johnson, B. Saigal, M. Talpaz, and N. J. Donato Dasatinib (BMS-354825) Tyrosine Kinase Inhibitor Suppresses Invasion and Induces Cell Cycle Arrest and Apoptosis of Head and Neck Squamous Cell Carcinoma and Non-Small Cell Lung Cancer Cells Clin. Cancer Res., October 1, 2005; 11(19): 6924 - 6932. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. E. Ducker, J. J. Upson, K. J. French, and C. D. Smith Two N-Myristoyltransferase Isozymes Play Unique Roles in Protein Myristoylation, Proliferation, and Apoptosis Mol. Cancer Res., August 1, 2005; 3(8): 463 - 476. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Golas, J. Lucas, C. Etienne, J. Golas, C. Discafani, L. Sridharan, E. Boghaert, K. Arndt, F. Ye, D. H. Boschelli, et al. SKI-606, a Src/Abl Inhibitor with In vivo Activity in Colon Tumor Xenograft Models Cancer Res., June 15, 2005; 65(12): 5358 - 5364. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Silver, H. Naora, J. Liu, W. Cheng, and D. J. Montell Activated Signal Transducer and Activator of Transcription (STAT) 3: Localization in Focal Adhesions and Function in Ovarian Cancer Cell Motility Cancer Res., May 15, 2004; 64(10): 3550 - 3558. [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 |
