ArticleJournal of the National Cancer Institute2015
Targeting Focal Adhesion Kinase and Resistance to mTOR Inhibition in Pancreatic Neuroendocrine Tumors.
Article in Journal of the National Cancer Institute, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
32 citing papers in PubMed, 47 citations in OpenAlex.
- Phase II Study of Defactinib (VS6063) in Patients With Tumors WithJCO precision oncology · 2024Trial
- Phase 2 study of the focal adhesion kinase inhibitor defactinib (VS-6063) in previously treated advanced KRAS mutant non-small cell lung cancer.Lung cancer (Amsterdam, Netherlands) · 2020Trial
- The STK33/mTORC1/S6K1/HIF-1α signalling axis drives glycolysis and progression in pancreatic neuroendocrine tumours.Journal of translational medicine · 2026Article
- Defactinib in Combination with Mitotane Can Be an Effective Treatment in Human Adrenocortical Carcinoma.International journal of molecular sciences · 2025Article
- Protective Autophagy Attenuates the Cytotoxicity of MTI-31 in Renal Cancer Cells by Activating the ERK Pathway.Applied biochemistry and biotechnology · 2024Article
- C1QA and COMP: plasma-based biomarkers for early diagnosis of pancreatic neuroendocrine tumors.Scientific reports · 2023Article
- Back to the future: targeting the extracellular matrix to treat systemic sclerosis.Nature reviews. Rheumatology · 2023Review
- High frequency of alternative splicing variants of the oncogene Focal Adhesion Kinase in neuroendocrine tumors of the pancreas and breast.Frontiers of medicine · 2023Article
- A systems biology approach to define mechanisms, phenotypes, and drivers in PanNETs with a personalized perspective.NPJ systems biology and applications · 2023Article
- Potential effective diagnostic biomarker in patients with primary and metastatic small intestinal neuroendocrine tumors.Frontiers in genetics · 2023Article
- RIOK3 promotes pancreatic ductal adenocarcinoma cell invasion and metastasis by stabilizing FAK.Heliyon · 2022Article
- Focal Adhesion Kinase Provides a Collateral Vulnerability That Can Be Leveraged to Improve mTORC1 Inhibitor Efficacy.Cancers · 2022Article
- Targeting the FAK-Src Complex in Desmoplastic Small Round Cell Tumors, Ewing Sarcoma, and Rhabdomyosarcoma.Sarcoma · 2022Article
- Focal adhesion kinase inhibitors, a heavy punch to cancer.Discover oncology · 2021Review
- Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK-YAP Signaling.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2021Article
- Radiosensitization by Kinase Inhibition Revealed by Phosphoproteomic Analysis of Pancreatic Cancer Cells.Molecular & cellular proteomics : MCP · 2020Article
- Inhibition of the mechanistic target of rapamycin induces cell survival via MAPK in tuberous sclerosis complex.Orphanet journal of rare diseases · 2020Article
- Adipose‑derived mesenchymal stem cells ameliorate dibutyltin dichloride‑induced chronic pancreatitis by inhibiting the PI3K/AKT/mTOR signaling pathway.Molecular medicine reports · 2020Article
- Protein Expression of Cyclin B1, Transferrin Receptor, and Fibronectin Is Correlated with the Prognosis of Adrenal Cortical Carcinoma.Endocrinology and metabolism (Seoul, Korea) · 2020Article
- PAK4-NAMPT Dual Inhibition as a Novel Strategy for Therapy Resistant Pancreatic Neuroendocrine Tumors.Cancers · 2019Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundFocal adhesion kinase (FAK) mediates survival of normal pancreatic islets through activation of AKT. Upon malignant transformation of islet cells into pancreatic neuroendocrine tumors (PanNETs), AKT is frequently overexpressed and mutations in the AKT/mTOR pathway are detected. Because mTOR inhibitors rarely induce PanNET tumor regression, partly because of feedback activation of AKT, novel combination strategies are needed to target FAK/AKT/mTOR signaling.
methodsWe characterized the activation of FAK in PanNETs using immunohistochemistry and Western blot analysis and tested the FAK inhibitor PF-04554878 in human PanNET cells in vitro and in vivo (at least three mice per group). In addition, we evaluated the effect of combined FAK and mTOR inhibition on PanNET viability and apoptosis. All statistical tests were two-sided.
resultsWe found that FAK is overexpressed and hyperphosphorylated in human PanNETs and that PF-04554878 strongly inhibited FAK (Tyr397) autophosphorylation in a dose-dependent manner. We found that PF-04554878 inhibited cell proliferation and clonogenicity and induced apoptosis in PanNET cells. Moreover, oral administration of PF-04554878 statistically significantly reduced tumor growth in a patient-derived xenograft model of PanNET (P = .02) and in a human PanNET xenograft model of peritoneal carcinomatosis (P = .03). Importantly, PF-04554878 synergized with the mTOR inhibitor everolimus by preventing feedback AKT activation.
conclusionsWe demonstrate for the first time that FAK is overexpressed in PanNETs and that inhibition of FAK activity induces apoptosis and inhibits PanNET proliferation. We found that the novel FAK inhibitor PF-04554878 synergizes with everolimus, a US Food and Drug Administration-approved agent for PanNETs. Our findings warrant the clinical investigation of combined FAK and mTOR inhibition in PanNETs.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.