A Allam Mohamed1,2,3, Andreas Thomsen1,4, Marie Follo5, Costantinos Zamboglou1,4, Peter Bronsert6, Hanan Mostafa2, Aber Amen2, Mohamed Mekawy2, Anca L Grosu1,4, Thomas B Brunner7,8,9. 1. Department of Radiation Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 2. Clinical Oncology and Nuclear Medicine Department, Assiut University Hospitals, Asyut, Egypt. 3. Department of Radiation Oncology, RWTH Aachen University, Aachen, Germany. 4. Partner Site Freiburg, German Cancer Consortium (DKTK), Freiburg, Germany. 5. Department of Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 6. Institute for Surgical Pathology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 7. Department of Radiation Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany. thomas.brunner@med.ovgu.de. 8. Partner Site Freiburg, German Cancer Consortium (DKTK), Freiburg, Germany. thomas.brunner@med.ovgu.de. 9. Department of Radiation Oncology, University of Magdeburg, Magdeburg, Germany. thomas.brunner@med.ovgu.de.
Abstract
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.
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 FAKtyrosine 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.
Authors: Asma Begum; Theodore Ewachiw; Clinton Jung; Ally Huang; K Jessica Norberg; Luigi Marchionni; Ross McMillan; Vesselin Penchev; N V Rajeshkumar; Anirban Maitra; Laura Wood; Chenguang Wang; Christopher Wolfgang; Ana DeJesus-Acosta; Daniel Laheru; Irina M Shapiro; Mahesh Padval; Jonathan A Pachter; David T Weaver; Zeshaan A Rasheed; William Matsui Journal: PLoS One Date: 2017-07-10 Impact factor: 3.240
Authors: Tina Jost; Barbara Schuster; Lucie Heinzerling; Thomas Weissmann; Rainer Fietkau; Luitpold V Distel; Markus Hecht Journal: Strahlenther Onkol Date: 2022-04-26 Impact factor: 4.033