3D cell cultures of human head and neck squamous cell carcinoma cells are radiosensitized by the focal adhesion kinase inhibitor TAE226.
OBJECTIVE
Focal adhesion kinase (FAK), a main player in integrin signaling and survival, is frequently overexpressed in human cancers and therefore postulated as potential target in cancer therapy. The aim of this study was to evaluate the radiosensitizing potential of the FAK inhibitor TAE226 in three-dimensional (3D) tumor cell cultures.


METHODS
Head and neck squamous cell carcinoma (HNSCC) cells (FaDu, UT-SCC15, UT-SCC45), lung cancer cells (A549), colorectal carcinoma cells (DLD-1, HCT-116) and pancreatic tumor cells (MiaPaCa2, Panc1) were treated with different concentrations of TAE226 (0-1mum; 1 or 24h) without or in combination with irradiation (0-6Gy, X-ray, single dose). Subsequently, 3D clonogenic survival assays (laminin-rich extracellular matrix) and Western blotting (expression/phosphorylation, e.g. FAK, Akt, ERK1/2) were performed.


RESULTS
All investigated 3D cell cultures showed a dose-dependent reduction in clonogenic survival by TAE226. Intriguingly, TAE226 only significantly radiosensitized 3D HNSCC cell cultures accompanied by a pronounced dephosphorylation of FAK, Akt and ERK1/2.


CONCLUSIONS
Our data demonstrate TAE226 as potent FAK inhibitor that enhances the cellular radiosensitivity particularly of HNSCC cells grown in a 3D cell culture model. Future in vitro and in vivo investigations will clarify, to which extent this approach might be clinically relevant for radiotherapy of HNSCC.
Hehlgans
Stephanie
S
OncoRay-Center for Radiation Research in Oncology, Dresden University of Technology, Dresden, Germany.
Lange
Inga
I
Eke
Iris
I
Cordes
Nils
N
D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000532:radiotherapy; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects* / Q000528:radiation effects*; D015179:Colorectal Neoplasms / Q000473:pathology / Q000532:radiotherapy; D004305:Dose-Response Relationship, Drug; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000532:radiotherapy; D009025:Morpholines / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000532:radiotherapy; D011336:Probability; D011836:Radiation Tolerance / Q000187:drug effects; D011839:Radiation, Ionizing; D014407:Tumor Cells, Cultured / Q000187:drug effects
D009025:Morpholines; C524632:TAE226; D051416:Focal Adhesion Protein-Tyrosine Kinases