{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T15:32:45Z","timestamp":1793287965667,"version":"4.5.0"},"reference-count":45,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T00:00:00Z","timestamp":1767052800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"Deutsche Forschungsgemeinschaft","award":["MO1018\/2-2"],"award-info":[{"award-number":["MO1018\/2-2"]}],"id":[{"id":"https:\/\/ror.org\/018mejw64","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Deutsche Forschungsgemeinschaft","award":["Project-ID 424957847-TRR 296 LOCOTACT"],"award-info":[{"award-number":["Project-ID 424957847-TRR 296 LOCOTACT"]}],"id":[{"id":"https:\/\/ror.org\/018mejw64","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Deutsche Forschungsgemeinschaft","award":["University Medicine Essen Clinician Scientist Prog"],"award-info":[{"award-number":["University Medicine Essen Clinician Scientist Prog"]}],"id":[{"id":"https:\/\/ror.org\/018mejw64","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Thyroid\u00ae"],"published-print":{"date-parts":[[2026,2,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      Anaplastic thyroid cancer (ATC) is the most aggressive thyroid cancer with a median survival of less than six months. So far, no therapies offering a survival benefit are established. Thus, new therapeutic approaches are urgently needed. In general, genetic alterations leading to ATC increase PI3K and MAPK\/ERK\u00a0signaling and include mutations in receptor tyrosine kinases and tumor suppressor genes. They often occur together with the loss of p53, the most prevalent mutation in human ATC. Among such alterations are mutations and rearrangements of the\n                      <jats:italic toggle=\"yes\">anaplastic lymphoma kinase<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">ALK<\/jats:italic>\n                      ) gene.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      To study ATC and potential treatment options, we generated a mouse model with inducible thyrocyte-specific expression of constitutively active mutant ALK\n                      <jats:sup>F1174L<\/jats:sup>\n                      and homozygous deletion of\n                      <jats:italic toggle=\"yes\">Trp53<\/jats:italic>\n                      due to a Cre recombinase under control of the\n                      <jats:italic toggle=\"yes\">thyroglobulin<\/jats:italic>\n                      promoter (thyroglobulin [Tg]-Cre\n                      <jats:sup>ERT2+\/0<\/jats:sup>\n                      ;lox-stop-lox (LSL)-ALK\n                      <jats:sup>F1174L\/+<\/jats:sup>\n                      ;Trp53\n                      <jats:sup>LoxP\/LoxP<\/jats:sup>\n                      mice, here referred to as Trp53\n                      <jats:sup>KO<\/jats:sup>\n                      \/ALK\n                      <jats:sup>F1174L<\/jats:sup>\n                      mice). Moreover, we established several primary thyroid cancer cell lines harboring ALK\n                      <jats:sup>F1174L<\/jats:sup>\n                      and Trp53\n                      <jats:sup>KO<\/jats:sup>\n                      and investigated the effects of ALK inhibition\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">in\u00a0vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Median survival of Trp53\n                      <jats:sup>KO<\/jats:sup>\n                      \/ALK\n                      <jats:sup>F1174L<\/jats:sup>\n                      mice was severely reduced, and the mice showed massively enlarged thyroids. Histopathology confirmed the development of locally invasive and metastatic ATC. Treatment of primary Trp53\n                      <jats:sup>KO<\/jats:sup>\n                      \/ALK\n                      <jats:sup>F1174L<\/jats:sup>\n                      ATC cells with the ALK inhibitor TAE-684 decreased AKT and ERK phosphorylation and induced a dose-dependent cytotoxicity. Trp53\n                      <jats:sup>KO<\/jats:sup>\n                      \/ALK\n                      <jats:sup>F1174L<\/jats:sup>\n                      mice treated with TAE-684 showed significantly extended median survival compared with the solvent group (66 days vs. 18 days,\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      &lt; 0.0001).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      Our data demonstrate that the combination of ALK\n                      <jats:sup>F1174L<\/jats:sup>\n                      mutation with\n                      <jats:italic toggle=\"yes\">Trp53<\/jats:italic>\n                      loss leads to the development of ATC. This study provides the first functional data supporting the use of ALK inhibitors in patients with\n                      <jats:italic toggle=\"yes\">ALK<\/jats:italic>\n                      -driven ATC. Our novel ATC mouse model and the derived cell lines offer valuable tools to explore the molecular characteristics of ATC, especially signaling pathway activation and tumor microenvironment, and to test novel therapeutics for the treatment of advanced thyroid cancers.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/10507256251409070","type":"journal-article","created":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T11:00:37Z","timestamp":1767092437000},"page":"177-187","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["ALK Inhibition Prolongs Survival in a Mouse Model of\n                    <i>ALK<\/i>\n                    -Positive Anaplastic Thyroid Cancer"],"prefix":"10.1177","volume":"36","author":[{"given":"Yara Maria","family":"Machlah","sequence":"first","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, Essen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Brandenburg","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, Essen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg Sebastian","family":"H\u00f6nes","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, Essen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Theurer","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian Dominic","family":"Prinz","sequence":"additional","affiliation":[{"name":"Institute for Artificial Intelligence in Medicine, University Hospital Essen, University of Duisburg Essen, Essen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Hoppe","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, Essen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feyza","family":"Cansiz","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, Essen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes H.","family":"Schulte","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology and Hematology, Charit\u00e9 University Medicine, Berlin, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jukka","family":"Kero","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Turku, Turku, Finland."},{"name":"Research Centre for Integrative Physiology and Pharmacology, Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hendrik","family":"Undeutsch","sequence":"additional","affiliation":[{"name":"Research Centre for Integrative Physiology and Pharmacology, Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Siveke","sequence":"additional","affiliation":[{"name":"Bridge Institute of Experimental Tumour Therapy, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"K\u00f6ster","sequence":"additional","affiliation":[{"name":"Institute for Artificial Intelligence in Medicine, University Hospital Essen, University of Duisburg Essen, Essen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dagmar","family":"Fuehrer","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, Essen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars C.","family":"Moeller","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, Essen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2025,12,30]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1530\/endoabs.92.OP-05-01"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","unstructured":"Machlah YM Brandenburg T H\u00f6nes GS et al. 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