Abstract
IntroductionFocal 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 materialsUsing 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.ResultsA 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.ConclusionPharmacological 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.
Highlights
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
Overexpression and genetic alterations of FAK in pancreatic ducal adenocarcinoma (PDAC) negatively impact outcome First, we examined FAK differential expression between PDAC and normal tissue using GEPIA server
PTK2 expression was significantly higher in PDAC samples (n = 179) in comparison to the normal pancreatic tissue samples (n = 171) (Fig. 1a) and this overexpression was not significantly different across the four tumor stages
Summary
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. Several reasons have been proposed to explain the poor prognosis These include lack of specific symptoms for early disease diagnosis, the complexity of the molecular survival mechanisms, and the desmoplastic reaction (DR), which protects cancer cells against the therapy and facilitates their invasion into neighboring structures [3,4,5]. While radiation therapy was shown to have little if any role in the first and last stages, the question of a potential benefit from radiotherapy in the borderline-resectable and locally advanced forms of the disease remains to be answered [7, 8]. Other studies did not conclude a benefit from adding chemoradiation in those stages [13] Such uncertainty about the role of radiation therapy in PDAC could be attributed to the poor understanding of the molecular complexity of radioresistance mechanisms in pancreatic cancer. We investigated the potential role of the focal adhesion kinase (FAK) in improving the radiosensitivity of PDAC
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