Inhibition of Src with AZD0530 reveals the Src-Focal Adhesion kinase complex as a novel therapeutic target in papillary and anaplastic thyroid cancer.
BACKGROUND
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.


METHODS
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.
Schweppe
Rebecca E
RE
Division of Endocrinology, Diabetes, and Metabolism, University of Colorado Denver, Aurora, Colorado 80045, USA. Rebecca.Schweppe@ucdenver.edu
Kerege
Anna A
AA
French
Jena D
JD
Sharma
Vibha
V
Grzywa
Rachel L
RL
Haugen
Bryan R
BR
D000970:Antineoplastic Agents / Q000627:therapeutic use; D052117:Benzodioxoles / Q000494:pharmacology / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism; D002291:Carcinoma, Papillary / Q000188:drug therapy* / Q000378:metabolism; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D052117:Benzodioxoles; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C515233:saracatinib; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src)