{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:45:35Z","timestamp":1792788335135,"version":"4.5.0"},"reference-count":58,"publisher":"The Company of Biologists","issue":"3","license":[{"start":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T00:00:00Z","timestamp":1774310400000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Swiss 3RCC"},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"crossref","award":["314061271 \u2013 TRR 205"],"award-info":[{"award-number":["314061271 \u2013 TRR 205"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"name":"USZ"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Pancreatic neuroendocrine tumors (pNETs) are rare tumors, often detected at advanced stages for which current therapies are mostly unsuccessful. Despite significant progress in the understanding of pathogenic molecular pathways, most single targeted treatments only slow disease progression while patients develop resistance due to compensatory mechanisms. To identify novel combination therapies, we assessed the effects of TNF\u03b1, insulin and GSK3 inhibition (GSK3i) in spheroids of the metastatic pNET model BON-1 on subcellular localization and activation of cell cycle components and apoptosis. While cyclin D1 and CDK4 and 6 (cyclin-dependent kinase) stainings, related protein levels and apoptosis were not affected or only weakly affected by single treatments, the combinatorial treatments acted synergistically to induce cell death, as assessed by cleaved caspase-3 immunopositivity. Protein levels of CDK4 and CDK6 were furthermore validated in primary pNET cultures. Compensatory mechanisms under the single treatments might include activation of CDK1\/2 and the DNA damage response, as assessed by the activation of phospho-Chk2, since this was perturbed under the combinatorial treatments. Taken together, our work identifies combinatorial treatments that substantially reduce the viability of spheroidal BON-1 cultures and patient-derived primary cultures as potential novel therapies for the treatment of pNETs.<\/jats:p>","DOI":"10.1242\/bio.062358","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T09:42:51Z","timestamp":1774345371000},"source":"Crossref","is-referenced-by-count":1,"title":["GSK3i combinatorial treatments affect CDK4\/6 and compensatory pathways in 3D preclinical models of pancreatic neuroendocrine tumors"],"prefix":"10.1242","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2575-7558","authenticated-orcid":false,"given":"Edlira","family":"Luca","sequence":"first","affiliation":[{"name":"University Hospital Zurich (USZ) and University of Zurich (UZH) 1 Department of Endocrinology, Diabetology and Clinical Nutrition , , 8091 Z\u00fcrich ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Shapiro","sequence":"additional","affiliation":[{"name":"University Hospital Zurich (USZ) and University of Zurich (UZH) 1 Department of Endocrinology, Diabetology and Clinical Nutrition , , 8091 Z\u00fcrich ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huguette","family":"Debaix","sequence":"additional","affiliation":[{"name":"University Hospital Zurich (USZ) and University of Zurich (UZH) 1 Department of Endocrinology, Diabetology and Clinical Nutrition , , 8091 Z\u00fcrich ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin","family":"Zitzmann","sequence":"additional","affiliation":[{"name":"LMU University Hospital, LMU Munich 2 Department of Medicine IV , , 80336 Munich ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Wang","sequence":"additional","affiliation":[{"name":"LMU University Hospital, LMU Munich 2 Department of Medicine IV , , 80336 Munich ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph J.","family":"Auernhammer","sequence":"additional","affiliation":[{"name":"LMU University Hospital, LMU Munich 2 Department of Medicine IV , , 80336 Munich ,","place":["Germany"]},{"name":"Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM, ENETS Center of Excellence), LMU University Hospital, LMU Munich 3 , 81377 Munich ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Beuschlein","sequence":"additional","affiliation":[{"name":"University Hospital Zurich (USZ) and University of Zurich (UZH) 1 Department of Endocrinology, Diabetology and Clinical Nutrition , , 8091 Z\u00fcrich ,","place":["Switzerland"]},{"name":"LMU University Hospital, LMU Munich 2 Department of Medicine IV , , 80336 Munich ,","place":["Germany"]},{"name":"The LOOP Zurich-Medical Research Center 4 , CH-8091 Zurich ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svenja","family":"N\u00f6lting","sequence":"additional","affiliation":[{"name":"University Hospital Zurich (USZ) and University of Zurich (UZH) 1 Department of Endocrinology, Diabetology and Clinical Nutrition , , 8091 Z\u00fcrich ,","place":["Switzerland"]},{"name":"LMU University Hospital, LMU Munich 2 Department of Medicine IV , , 80336 Munich ,","place":["Germany"]},{"name":"ENETS Center of Excellence Zurich, University Hospital Zurich 5 , CH-8091 Zurich ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constanze","family":"Hantel","sequence":"additional","affiliation":[{"name":"University Hospital Zurich (USZ) and University of Zurich (UZH) 1 Department of Endocrinology, Diabetology and Clinical Nutrition , , 8091 Z\u00fcrich ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2026,3,24]]},"reference":[{"key":"2026032405424498600_BIO062358C1","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1007\/s10555-024-10206-6","article-title":"Tumor necrosis factor superfamily signaling: life and death in cancer","volume":"43","author":"Ababneh","year":"2024","journal-title":"Cancer Metastasis Rev."},{"key":"2026032405424498600_BIO062358C2","doi-asserted-by":"publisher","first-page":"8154","DOI":"10.1038\/ncomms9154","article-title":"Kinase-independent role for CRAF-driving tumour radioresistance via CHK2","volume":"6","author":"Advani","year":"2015","journal-title":"Nat. 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