{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T18:17:58Z","timestamp":1783448278026,"version":"3.55.0"},"reference-count":42,"publisher":"Bioscientifica","issue":"1","license":[{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"vor","delay-in-days":424,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,1,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Gastrointestinal neuroendocrine tumors (GI-NETs) are rare neoplasms with limited therapeutic options and increasing clinical incidence. Focal adhesion kinase (FAK) has been implicated in oncogenic processes across various tumor types; however, its specific role in GI-NET biology remains inadequately characterized. This study investigates the impact of FAK inhibition on GI-NET cell survival, invasive potential, and gene regulation, with the aim of evaluating FAK as a therapeutic target.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Human GI-NET cell lines (GOT1 and COLO320DM) were treated with Y15, a kinase inhibitor, and PROTAC-FAK (BI-0319), a degrader that abrogates both enzymatic and scaffold functions. siRNA-mediated knockdown of FAK was employed for functional validation. Assays assessing viability and apoptosis were performed in both 2D and 3D culture conditions, while invasion and colony formation were assessed in 2D culture. Western blotting, immunofluorescence, and qRT-PCR were used to evaluate molecular effects. Public transcriptomic datasets were analyzed to assess PTK2 expression across NET subtypes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>FAK inhibition reduced cell viability, colony formation, and invasive capacity. PROTAC-FAK, but not Y15, decreased H3K9 acetylation, indicating scaffold-dependent epigenetic modulation. On the other hand, both PROTAC-FAK and Y15 decreased H3K4 methylation levels, further supporting the role of FAK in chromatin regulation. Both compounds suppressed ERK1\/2 phosphorylation and modulated RB1 expression, which was further validated by FAK knockdown. In silico analysis revealed elevated PTK2 expression in rectal and small intestinal NETs relative to pancreatic NETs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings identify FAK as a regulator of oncogenic and epigenetic pathways in GI-NETs and support its therapeutic targeting, particularly through degradation strategies that inhibit its non-catalytic functions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1530\/eo-25-0052","type":"journal-article","created":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T14:19:37Z","timestamp":1753971577000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-15","source":"Crossref","is-referenced-by-count":1,"title":["FAK inhibition disrupts tumor growth, apoptosis, and transcriptional regulation in GI-NETs"],"prefix":"10.1530","volume":"5","author":[{"given":"Lara","family":"Toffoli","sequence":"first","affiliation":[{"name":"Cancer Cell Signalling Lab, University of Udine 1 , ,","place":["Udine, Italy"]},{"name":"Department of Medicine, University of Udine 2 , ,","place":["Udine, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angeliki","family":"Ditsiou","sequence":"additional","affiliation":[{"name":"Cancer Cell Signalling Lab, University of Udine 1 , ,","place":["Udine, Italy"]},{"name":"Department of Medicine, University of Udine 2 , ,","place":["Udine, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1261-0637","authenticated-orcid":true,"given":"Luca","family":"Triboli","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Udine 2 , ,","place":["Udine, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victorine","family":"Hamm","sequence":"additional","affiliation":[{"name":"Cancer Cell Signalling Lab, University of Udine 1 , ,","place":["Udine, Italy"]},{"name":"\u00c9cole de Biologie Industrielle 3 , ,","place":["Cergy, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Moschioni","sequence":"additional","affiliation":[{"name":"Cancer Cell Signalling Lab, University of Udine 1 , ,","place":["Udine, Italy"]},{"name":"ASUFC 4 , , ,","place":["Latisana, Udine, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"D\u2019Este","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Udine 2 , ,","place":["Udine, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4877-6292","authenticated-orcid":true,"given":"Teresa","family":"Gagliano","sequence":"additional","affiliation":[{"name":"Cancer Cell Signalling Lab, University of Udine 1 , ,","place":["Udine, Italy"]},{"name":"Department of Medicine, University of Udine 2 , ,","place":["Udine, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","published-online":{"date-parts":[[2025,7,31]]},"reference":[{"key":"2026070713301620600_bib1","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1038\/s41588-018-0138-4","article-title":"A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors","volume":"50","author":"Alvarez","year":"2018","journal-title":"Nat Genet"},{"key":"2026070713301620600_bib3","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1530\/EC-19-0192","article-title":"EGF and IGF1 affect sunitinib activity in BP-NEN: new putative targets beyond VEGFR?","volume":"8","author":"Bresciani","year":"2019","journal-title":"Endocr Connections"},{"key":"2026070713301620600_bib4","doi-asserted-by":"crossref","DOI":"10.3389\/fendo.2019.00682","article-title":"Evaluation of spheroid 3D culture methods to study a pancreatic neuroendocrine neoplasm cell line","volume":"10","author":"Bresciani","year":"2019","journal-title":"Front Endocrinol"},{"key":"2026070713301620600_bib5","doi-asserted-by":"crossref","DOI":"10.3389\/fonc.2022.901435","article-title":"Epigenetic regulation in gastroenteropancreatic neuroendocrine tumors","volume":"12","author":"Crabtree","year":"2022","journal-title":"Front Oncol"},{"key":"2026070713301620600_bib6","doi-asserted-by":"crossref","first-page":"17019","DOI":"10.1021\/jacs.8b08008","article-title":"Addressing kinase-independent functions of Fak via PROTAC-mediated degradation","volume":"140","author":"Cromm","year":"2018","journal-title":"J Am Chem Soc"},{"key":"2026070713301620600_bib7","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1158\/1535-7163.MCT-19-0330","article-title":"A synergistic anticancer FAK and HDAC inhibitor combination discovered by a novel chemical\u2013genetic high-content phenotypic screen","volume":"19","author":"Dawson","year":"2020","journal-title":"Mol Cancer Therapeut"},{"key":"2026070713301620600_bib8","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/s41568-021-00340-6","article-title":"Targeting FAK in anticancer combination therapies","volume":"21","author":"Dawson","year":"2021","journal-title":"Nat Rev Cancer"},{"key":"2026070713301620600_bib9","doi-asserted-by":"crossref","first-page":"R315","DOI":"10.1530\/ERC-17-0012","article-title":"Genetic and epigenetic drivers of neuroendocrine tumours (NET)","volume":"24","author":"Di Domenico","year":"2017","journal-title":"Endocr Relat Cancer"},{"key":"2026070713301620600_bib10","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.abc3099","article-title":"The structure-function relationship of oncogenic LMTK3","volume":"6","author":"Ditsiou","year":"2020","journal-title":"Sci Adv"},{"key":"2026070713301620600_bib11","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1038\/s41418-022-00988-z","article-title":"Cell cycle regulation: P53-p21-RB signaling","volume":"29","author":"Engeland","year":"2022","journal-title":"Cell Death Differ"},{"key":"2026070713301620600_bib12","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/s41417-020-00260-x","article-title":"Targeting histone deacetylases for combination therapies in neuroendocrine tumors","volume":"28","author":"Gagliano","year":"2021","journal-title":"Cancer Gene Ther"},{"key":"2026070713301620600_bib13","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1530\/ERC-13-0042","article-title":"mTOR, p70S6K, AKT, and ERK1\/2 levels predict sensitivity to mTOR and PI3K\/mTOR inhibitors in human bronchial carcinoids","volume":"20","author":"Gagliano","year":"2013","journal-title":"Endocr Relat Cancer"},{"key":"2026070713301620600_bib14","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.bcp.2015.10.012","article-title":"Inhibition of epithelial growth factor receptor can play an important role in reducing cell growth and survival in adrenocortical tumors","volume":"98","author":"Gagliano","year":"2015","journal-title":"Biochem Pharmacol"},{"key":"2026070713301620600_bib15","doi-asserted-by":"crossref","first-page":"3188","DOI":"10.1172\/JCI128313","article-title":"PIK3C\u03b4 expression by fibroblasts promotes triple-negative breast cancer progression","volume":"130","author":"Gagliano","year":"2020","journal-title":"J Clin Investig"},{"key":"2026070713301620600_bib16","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1210\/endrev\/bnad006","article-title":"Advances in the treatment of gastroenteropancreatic neuroendocrine carcinomas: are we moving forward?","volume":"44","author":"Garcia-Carbonero","year":"2023","journal-title":"Endocr Rev"},{"key":"2026070713301620600_bib17","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/s41598-020-80111-9","article-title":"FAK regulates IL-33 expression by controlling chromatin accessibility at c-Jun motifs","volume":"11","author":"Griffith","year":"2021","journal-title":"Sci Rep"},{"key":"2026070713301620600_bib18","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1530\/ERC-17-0445","article-title":"The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines","volume":"25","author":"Hofving","year":"2018","journal-title":"Endocr Relat Cancer"},{"key":"2026070713301620600_bib19","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.mce.2011.11.024","article-title":"Synergistic anti-tumor effects of RAD001 with MEK inhibitors in neuroendocrine tumors: a potential mechanism of therapeutic limitation of mTOR inhibitor","volume":"350","author":"Iida","year":"2012","journal-title":"Mol Cell Endocrinol"},{"key":"2026070713301620600_bib20","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1159\/000494258","article-title":"Unmet needs in functional and nonfunctional pancreatic neuroendocrine neoplasms","volume":"108","author":"Jensen","year":"2019","journal-title":"Neuroendocrinology"},{"key":"2026070713301620600_bib21","doi-asserted-by":"crossref","first-page":"e215","DOI":"10.1161\/CIRCRESAHA.121.319066","article-title":"FAK activation promotes SMC dedifferentiation via increased DNA methylation in contractile genes","volume":"129","author":"Jeong","year":"2021","journal-title":"Circ Res"},{"key":"2026070713301620600_bib22","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/S0002-9440(10)64017-5","article-title":"A transplantable human carcinoid as model for somatostatin receptor-mediated and amine transporter-mediated radionuclide uptake","volume":"158","author":"K\u00f6lby","year":"2001","journal-title":"Am J Pathol"},{"key":"2026070713301620600_bib23","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1016\/j.cell.2007.05.041","article-title":"Structural basis for the autoinhibition of focal adhesion kinase","volume":"129","author":"Lietha","year":"2007","journal-title":"Cell"},{"key":"2026070713301620600_bib24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10059-013-0139-1","article-title":"Nuclear FAK: a new mode of gene regulation from cellular adhesions","volume":"36","author":"Lim","year":"2013","journal-title":"Mol Cells"},{"key":"2026070713301620600_bib25","doi-asserted-by":"crossref","first-page":"21526","DOI":"10.1074\/jbc.M110.129999","article-title":"Knock-in mutation reveals an essential role for focal adhesion kinase activity in blood vessel morphogenesis and cell motility-polarity but not cell proliferation","volume":"285","author":"Lim","year":"2010","journal-title":"J Biol Chem"},{"key":"2026070713301620600_bib26","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1038\/s12276-020-0447-4","article-title":"Targeting focal adhesion kinase in cancer cells and the tumor microenvironment","volume":"52","author":"Murphy","year":"2020","journal-title":"Exp Mol Med"},{"key":"2026070713301620600_bib27","doi-asserted-by":"crossref","DOI":"10.1016\/j.isci.2021.102807","article-title":"Identification of response signatures for tankyrase inhibitor treatment in tumor cell lines","volume":"24","author":"Mygland","year":"2021","journal-title":"iScience"},{"key":"2026070713301620600_bib28","doi-asserted-by":"crossref","first-page":"5731","DOI":"10.18632\/oncotarget.27184","article-title":"A side-by-side evaluation of [18F]FDOPA enantiomers for non-invasive detection of neuroendocrine tumors by positron emission tomography","volume":"10","author":"Narayan","year":"2019","journal-title":"Oncotarget"},{"key":"2026070713301620600_bib29","doi-asserted-by":"crossref","first-page":"2508","DOI":"10.1021\/acs.jmedchem.8b01826","article-title":"Highly selective PTK2 proteolysis targeting chimeras to probe focal adhesion kinase scaffolding functions","volume":"62","author":"Popow","year":"2019","journal-title":"J Med Chem"},{"key":"2026070713301620600_bib30","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1159\/000500591","article-title":"Strong antitumor activity of bevacizumab and aflibercept in neuroendocrine carcinomas: in-depth preclinical study","volume":"110","author":"Rodr\u00edguez-Rem\u00edrez","year":"2020","journal-title":"Neuroendocrinology"},{"key":"2026070713301620600_bib31","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.cell.2018.03.035","article-title":"Oncogenic signaling pathways in the cancer genome atlas","volume":"173","author":"Sanchez-Vega","year":"2018","journal-title":"Cell"},{"key":"2026070713301620600_bib32","doi-asserted-by":"crossref","first-page":"3282","DOI":"10.1038\/s41467-020-17099-3","article-title":"A FAK\/HDAC5 signaling axis controls osteocyte mechanotransduction","volume":"11","author":"Sato","year":"2020","journal-title":"Nat Commun"},{"key":"2026070713301620600_bib2","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/nature21063","article-title":"Whole-genome landscape of pancreatic neuroendocrine tumours","volume":"543","author":"Scarpa","year":"2017","journal-title":"Nature"},{"key":"2026070713301620600_bib33","doi-asserted-by":"crossref","DOI":"10.1242\/jcs.261723","article-title":"Focal adhesion kinase signaling \u2013 tumor vulnerabilities and clinical opportunities","volume":"137","author":"Schlaepfer","year":"2024","journal-title":"J Cell Sci"},{"key":"2026070713301620600_bib34","doi-asserted-by":"crossref","first-page":"3113","DOI":"10.1038\/s41388-018-0197-0","article-title":"LMTK3 confers chemo-resistance in breast cancer","volume":"37","author":"Stebbing","year":"2018","journal-title":"Oncogene"},{"key":"2026070713301620600_bib35","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1002\/1878-0261.12610","article-title":"Focal adhesion kinase confers pro-migratory and antiapoptotic properties and is a potential therapeutic target in Ewing sarcoma","volume":"14","author":"Steinestel","year":"2020","journal-title":"Mol Oncol"},{"key":"2026070713301620600_bib36","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1038\/nrc3792","article-title":"FAK in cancer: mechanistic findings and clinical applications","volume":"14","author":"Sulzmaier","year":"2014","journal-title":"Nat Rev Cancer"},{"key":"2026070713301620600_bib37","article-title":"Mechanism and application of feedback loops formed by mechanotransduction and histone modifications","volume":"11","author":"Sun","year":"2024","journal-title":"Genes Dis"},{"key":"2026070713301620600_bib38","doi-asserted-by":"crossref","first-page":"145","DOI":"10.3390\/receptors3020008","article-title":"Exploring emerging therapeutic targets and opportunities in neuroendocrine tumors: updates on receptor tyrosine kinases","volume":"3","author":"Toffoli","year":"2024","journal-title":"Receptors"},{"key":"2026070713301620600_bib39","doi-asserted-by":"crossref","DOI":"10.1002\/advs.202306027","article-title":"Kinome-wide synthetic lethal screen identifies PANK4 as a modulator of temozolomide resistance in glioblastoma","volume":"11","author":"Vella","year":"2024","journal-title":"Adv Sci"},{"key":"2026070713301620600_bib40","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/bjc.2016.190","article-title":"Efficacy of focal adhesion kinase inhibition in non-small cell lung cancer with oncogenically activated MAPK pathways","volume":"115","author":"Zhang","year":"2016","journal-title":"Br J Cancer"},{"key":"2026070713301620600_bib41","article-title":"FAK-mediated phosphorylation at Y464 regulates p85\u03b2 nuclear translocation to promote tumorigenesis of ccRCC by repressing RB1 expression","volume":"42","author":"Zhang","year":"2023","journal-title":"Cell Rep"},{"key":"2026070713301620600_bib42","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.1083\/jcb.143.7.1997","article-title":"Regulation of the cell cycle by focal adhesion kinase","volume":"143","author":"Zhao","year":"1998","journal-title":"J Cell Biol"}],"container-title":["Endocrine Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/eo.bioscientifica.com\/view\/journals\/eo\/5\/1\/EO-25-0052.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/eo.bioscientifica.com\/downloadpdf\/journals\/eo\/5\/1\/EO-25-0052.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/eo\/article-pdf\/doi\/10.1530\/EO-25-0052\/194793\/eo-25-0052.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/eo\/article-pdf\/doi\/10.1530\/EO-25-0052\/194793\/eo-25-0052.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T17:51:40Z","timestamp":1783446700000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.bioscientifica.com\/eo\/article\/5\/1\/e250052\/34876\/FAK-inhibition-disrupts-tumor-growth-apoptosis-and"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,1]]},"references-count":42,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,1,1]]}},"URL":"https:\/\/doi.org\/10.1530\/eo-25-0052","relation":{},"ISSN":["2634-4793"],"issn-type":[{"value":"2634-4793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,1]]},"article-number":"e250052"}}