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

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

SUBMITTER: Schweppe RE

PROVIDER: S-EPMC2690419 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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

Schweppe Rebecca E RE Kerege Anna A AA French Jena D JD Sharma Vibha V Grzywa Rachel L RL Haugen Bryan R BR

The Journal of clinical endocrinology and metabolism 20090317 6

<h4>Context</h4>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).<h4>Objective</h4>The goal of this study was to determine the role of Src and FAK in the growth and invasion of PTC and ATC.<h4>Design</h4>PTC and ATC cells were treated with the oral Src inhibitor, AZD0530, to determine the consequenc ...[more]

PMID: 19293266

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Project description:Background: Anaplastic thyroid cancer (ATC) is a rare cancer with poor prognosis and few treatment options. The objective of this study was to investigate new immune-associated therapeutic targets by identifying ATC-derived, human leukocyte antigen (HLA) class II-presenting peptides. One protein that generated multiple peptides in ATC was chondroitin sulfate-proteoglycan-4 (CSPG4), a transmembrane proteoglycan with increased expression in multiple aggressive cancers, but not yet investigated in ATC. Methods: We applied autologous peripheral blood T cells to ATC patient-derived xenografted mice to examine whether ATC induces a tumor-specific T cell response. We then identified peptide antigens eluted from the HLA-DQ complex in ATC patient-derived cells using mass spectrometry, detecting abundant CSPG4-derived peptides specific to the ATC sample. Next, we analyzed the surface expression level of CSPG4 in thyroid cancer cell lines and primary cell culture using flow cytometry. In addition, we used immunohistochemistry to compare the expression level and localization of the CSPG4 protein in ATC, papillary thyroid cancer, and normal thyroid tissue. We then investigated the correlation between CSPG4 expression and clinicopathological features of patients with thyroid cancer. Results: We found that ATC tissue had a high level of HLA-DQ expression and that the patient's CD4+ T cells showed activation when exposed to ATC. By eluting the HLA-DQ complex of ATC tissue, we found that CSPG4 generated one of the most abundant and specific peptides. CSPG4 expression at the cell surface of thyroid cancer was also significantly high when determined by flow cytometry, with the majority of ATC cell lines exhibiting ∼10-fold higher mean fluorescence intensity. Furthermore, most ATC patient cases expressed CSPG4 in the cytoplasm or membrane of the tumor cells. CSPG4 expression was correlated with tumor size, extrathyroidal extension, and intercellular adhesion molecule-1 (ICAM-1) circumferential expression. CSPG4 mRNA overexpression was associated with worse overall survival in patients with ATC and poorly differentiated thyroid cancer. Conclusions: CSPG4 expression is significantly elevated in aggressive thyroid cancers, with a strong correlation with a poor prognosis. The vast number of HLA-DQ eluted CSPG4 peptides was identified in ATC, demonstrating the potential of CSPG4 as a novel immunotherapeutic target for ATC.

Dataset Information

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

Publications

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

Similar Datasets

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