FAK inhibition radiosensitizes pancreatic ductal adenocarcinoma cells in vitro

Introduction Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase protein frequently overexpressed in cancer and has been linked to an increase in the stem cell population of tumors, resistance to therapy, and metastatic spread. Pharmacological FAK inhibition in pancreatic cancer has receive...

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Published in:	Strahlentherapie und Onkologie Vol. 197; no. 1; pp. 27 - 38
Main Authors:	Mohamed, A. Allam, Thomsen, Andreas, Follo, Marie, Zamboglou, Costantinos, Bronsert, Peter, Mostafa, Hanan, Amen, Aber, Mekawy, Mohamed, Grosu, Anca L., Brunner, Thomas B.
Format:	Journal Article
Language:	English
Published:	Berlin/Heidelberg Springer Berlin Heidelberg 01-01-2021 Springer Nature B.V
Subjects:	Aminopyridines - pharmacology Antineoplastic Agents - pharmacology Biotechnology Cancer Cancer therapies Carcinoma, Pancreatic Ductal - drug therapy Carcinoma, Pancreatic Ductal - enzymology Cell Cycle - drug effects Cell Line, Tumor Coculture Techniques Collagen - metabolism Extracellular Matrix Proteins - metabolism Focal Adhesion Kinase 1 - antagonists & inhibitors Gene expression Histones - analysis Humans Kaplan-Meier Estimate Kinases Medicine Medicine & Public Health Neoplasm Proteins - antagonists & inhibitors Oncology Original Original Article Pancreatic cancer Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - enzymology Pancreatic Stellate Cells - drug effects Pancreatic Stellate Cells - metabolism Pharmacology Phosphorylation Progression-Free Survival Protein Kinase Inhibitors - pharmacology Radiation therapy Radiation Tolerance - drug effects Radiation-Sensitizing Agents - pharmacology Radiotherapy RNA Interference RNA, Messenger - biosynthesis RNA, Neoplasm - biosynthesis RNA, Small Interfering - genetics RNA, Small Interfering - pharmacology Spheroids, Cellular - drug effects Spheroids, Cellular - radiation effects Stem cells Stromal Cells - drug effects Survival Three dimensional models Tumor Stem Cell Assay Tumors Two dimensional models Tyrosine Stroma Radiosensitization Focal adhesion kinase Microenvironment Pancreatic ductal adenocarcinoma Pancreatic stellate cell
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Summary:	Introduction Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase protein frequently overexpressed in cancer and has been linked to an increase in the stem cell population of tumors, resistance to therapy, and metastatic spread. Pharmacological FAK inhibition in pancreatic cancer has received increased attention over the last few years, either alone or in combination with other therapeutics including chemotherapy and immunotherapy. However, its prognostic value and its role in radioresistance of pancreatic ducal adenocarcinoma (PDAC) is unknown. Methods and materials Using the TCGA and GTEx databases, we investigated the genetic alterations and mRNA expression levels of PTK2 (the encoding-gene for FAK) in normal pancreatic tissue and pancreatic cancer and its impact on patient survival. Furthermore, we evaluated the expression of FAK and its tyrosine domain Ty-397 in three pancreatic cancer cell lines. We went further and evaluated the role of a commercial FAK tyrosine kinase inhibitor VS-4718 on the viability and radiosensitization of the pancreatic cell lines as well as its effect on the extracellular matrix (ECM) production from the pancreatic stellate cells. Furthermore, we tested the effect of combining radiation with VS-4718 in a three-dimensional (3D) multicellular pancreatic tumor spheroid model. Results A database analysis revealed a relevant increase in genetic alterations and mRNA expression of the PTK2 in PDAC, which were associated with lower progression-free survival . In vitro, there was only variation in the basal phosphorylation level of FAK in cell lines. VS-4718 radiosensitized pancreatic cell lines only in the presence of ECM-producing pancreatic stellate cells and markedly reduced the ECM production in the stromal cells. Finally, using a 3D multicellular tumor model, the combination of VS-4718 and radiotherapy significantly reduced the growth of tumor aggregates. Conclusion Pharmacological inhibition of FAK in pancreatic cancer could be a novel therapeutic strategy as our results show a radiosensitization effect of VS-4718 in vitro in a multicellular 2D- and in a 3D-model of pancreatic cancer.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0179-7158 1439-099X
DOI:	10.1007/s00066-020-01666-0