pnd-1186 and Carcinoma--Pancreatic-Ductal

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.. 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.. 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.. 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.

Topics: Aminopyridines; Antineoplastic Agents; Carcinoma, Pancreatic Ductal; Cell Cycle; Cell Line, Tumor; Coculture Techniques; Collagen; Extracellular Matrix Proteins; Focal Adhesion Kinase 1; Histones; Humans; Kaplan-Meier Estimate; Neoplasm Proteins; Pancreatic Neoplasms; Pancreatic Stellate Cells; Progression-Free Survival; Protein Kinase Inhibitors; Radiation Tolerance; Radiation-Sensitizing Agents; RNA Interference; RNA, Messenger; RNA, Neoplasm; RNA, Small Interfering; Spheroids, Cellular; Stromal Cells; Tumor Stem Cell Assay

We investigated how pancreatic cancer developed resistance to focal adhesion kinase (FAK) inhibition over time.. Pancreatic ductal adenocarcinoma (PDAC) tumours from KPC mice (p48-CRE; LSL-KRas. Stromal depletion by FAK inhibitor therapy leads to eventual treatment resistance through the activation of STAT3 signalling. These data suggest that, similar to tumour-targeted therapies, resistance mechanisms to therapies targeting stromal desmoplasia may be critical to treatment durability.

Topics: Aminopyridines; Animals; Antineoplastic Agents; Carcinoma, Pancreatic Ductal; Collagen; Down-Regulation; Drug Resistance, Neoplasm; Female; Fibroblasts; Focal Adhesion Protein-Tyrosine Kinases; Humans; Mice, Inbred Strains; Pancreatic Neoplasms; Signal Transduction; Smad3 Protein; STAT3 Transcription Factor; Stromal Cells; Transforming Growth Factor beta; Xenograft Model Antitumor Assays

Single-agent immunotherapy has achieved limited clinical benefit to date in patients with pancreatic ductal adenocarcinoma (PDAC). This may be a result of the presence of a uniquely immunosuppressive tumor microenvironment (TME). Critical obstacles to immunotherapy in PDAC tumors include a high number of tumor-associated immunosuppressive cells and a uniquely desmoplastic stroma that functions as a barrier to T cell infiltration. We identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as an important regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlated with high levels of fibrosis and poor CD8(+) cytotoxic T cell infiltration. Single-agent FAK inhibition using the selective FAK inhibitor VS-4718 substantially limited tumor progression, resulting in a doubling of survival in the p48-Cre;LSL-Kras(G12D);Trp53(flox/+) (KPC) mouse model of human PDAC. This delay in tumor progression was associated with markedly reduced tumor fibrosis and decreased numbers of tumor-infiltrating immunosuppressive cells. We also found that FAK inhibition rendered the previously unresponsive KPC mouse model responsive to T cell immunotherapy and PD-1 antagonists. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME and renders tumors responsive to immunotherapy.

Topics: Aminopyridines; Animals; Antimetabolites, Antineoplastic; Carcinoma, Pancreatic Ductal; CD8-Positive T-Lymphocytes; Cell Proliferation; Deoxycytidine; Disease Models, Animal; Disease Progression; Fibrosis; Focal Adhesion Protein-Tyrosine Kinases; Gemcitabine; Humans; Immunoblotting; Immunohistochemistry; Immunotherapy; Immunotherapy, Adoptive; Mice; Pancreatic Neoplasms; Programmed Cell Death 1 Receptor; Reverse Transcriptase Polymerase Chain Reaction; Tumor Escape; Tumor Microenvironment