This Article Full Text Full Text (PDF) Supplemental Data Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Google Scholar Articles by Schweppe, R. E. Articles by Haugen, B. R. PubMed PubMed Citation Articles by Schweppe, R. E. Articles by Haugen, B. R. Related Collections Thyroid Endocrine Oncology

Inhibition of Src with AZD0530 Reveals the Src-Focal Adhesion Kinase Complex as a Novel Therapeutic Target in Papillary and Anaplastic Thyroid Cancer

Division of Endocrinology, Diabetes, and Metabolism, University of Colorado Denver, Aurora, Colorado 80045

Address all correspondence and requests for reprints to: Rebecca E. Schweppe, Ph.D., Division of Endocrinology, Diabetes, and Metabolism, University of Colorado Denver, Aurora, Colorado 80045. E-mail: Rebecca.Schweppe{at}ucdenver.edu.

Context: Focal adhesion kinase (FAK) and Src are overexpressed and activated in many cancers and have been associated with tumor progression. The role of the Src-FAK complex has not been characterized in papillary and anaplastic thyroid cancer (PTC and ATC).

Objective: The goal of this study was to determine the role of Src and FAK in the growth and invasion of PTC and ATC.

Design: PTC and ATC cells were treated with the oral Src inhibitor, AZD0530, to determine the consequences of Src inhibition using growth and invasion assays. FAK and phospho-FAK levels were analyzed in cell lines as well as in PTC tumor samples.

Results: AZD0530 treatment inhibited the growth and invasion in four of five thyroid cancer cell lines, and inhibition did not correlate with basal levels of phospho-Src. Instead, we show for the first time that FAK, a critical substrate and effector of Src, is phosphorylated at tyrosine residue 861 (pY861) in PTC and ATC cells, and high levels of phospho-FAK correlate with AZD0530 sensitivity. We further showed that pY861-FAK phosphorylation is Src-dependent. Sensitivity to AZD0530 was confirmed using a preclinical three-dimensional culture model. Phospho-ERK1/2 was not affected by AZD0530, indicating that Src signaling does not require MAPK. Finally, FAK and pY861-FAK were expressed in 10 of 10 and five of 10 PTC tumors, respectively.

Conclusions: Inhibition of the Src-FAK complex represents a promising therapeutic strategy for patients with advanced thyroid cancer, and phospho-FAK represents a potential biomarker for response.

This article has been cited by other articles:

				H. T. Ngo, A. K. Azab, M. Farag, X. Jia, M. M. Melhem, J. Runnels, A. M. Roccaro, F. Azab, A. Sacco, X. Leleu, et al. Src Tyrosine Kinase Regulates Adhesion and Chemotaxis in Waldenstrom Macroglobulinemia Clin. Cancer Res., October 1, 2009; 15(19): 6035 - 6041. [Abstract] [Full Text] [PDF]