{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:40:13Z","timestamp":1792521613120,"version":"4.5.0"},"reference-count":11,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:00:00Z","timestamp":1792454400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:00:00Z","timestamp":1792454400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Wilhelm-Roux-Program","award":["FKZ 32\/11"],"award-info":[{"award-number":["FKZ 32\/11"]}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SE 581\/33-1"],"award-info":[{"award-number":["SE 581\/33-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["ZS\/2024\/01\/183830"],"award-info":[{"award-number":["ZS\/2024\/01\/183830"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Exp Hematol Oncol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Anaplastic thyroid carcinoma is one of the most aggressive thyroid cancers characterized by rapid progression and high resistance to conventional therapies. Although mutations in the BRAF gene are common in thyroid cancer, targeted therapies against this mutation show limited clinical benefit. This study investigated whether inhibition of downstream signaling pathways using the selected MEK inhibitor cobimetinib provides advantages over direct BRAF inhibition. Genomic and expression analyses of thyroid cancer datasets confirmed frequent BRAF alterations and activation of MAPK-pathway-associated signaling. Functional studies using thyroid cancer cell lines demonstrated that cobimetinib more effectively reduced MAPK pathway activity specifically reducing ERK1\/2 phosphorylation compared to direct BRAF inhibition. This pathway suppression was associated with decreased tumor cell invasion, migration, and expression of epithelial\u2013mesenchymal transition markers, alongside increased induction of late apoptosis. Furthermore, cobimetinib altered immune-related features of tumor cells by reducing expression of immune inhibitory molecules and cytokine secretion, while simultaneously enhancing expression of molecules involved in antigen presentation, such as HLA-ABC. Co-culture experiments with human fibroblasts showed that cobimetinib modulates tumor\u2013fibroblast communication and fibroblast phenotype composition. Cobimetinib reduced the formation of specific immune-suppressive fibroblast subtypes, whereas exposure to interleukin-8 promoted their development and increased tumor cell migration. Secretome profiling confirmed that cobimetinib markedly depleted pro-tumorigenic cytokines, particularly reducing IL-8 secretion. While data provide preclinical evidence that downstream MEK inhibition alters tumor cell signaling and IL-8-associated tumor\u2013fibroblast communication in ATC-centered models, they do not establish cobimetinib monotherapy as a replacement for clinically established BRAF\/MEK combination therapies. Instead, these data support the broader therapeutic potential of MEK inhibitors as a strategy to target both tumor progression and immune evasion in aggressive endocrine malignancies.<\/jats:p>","DOI":"10.1186\/s40164-026-00839-4","type":"journal-article","created":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T05:19:49Z","timestamp":1792473589000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cobimetinib impairs tumor survival and immune escape by altering my-CAFs in BRAFV600E-mutated anaplastic thyroid carcinoma"],"prefix":"10.1186","volume":"15","author":[{"given":"Mario","family":"Udinotti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niclas","family":"Ramm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thamer Abed Alhaleem Amin","family":"Hamdan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad Sameer Ali","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Udo","family":"Siebolts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Bauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"Lorenz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Dierks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Wickenhauser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Seliger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,20]]},"reference":[{"issue":"1","key":"839_CR1","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/s12022-022-09707-3","volume":"33","author":"ZW Baloch","year":"2022","unstructured":"Baloch ZW, Asa SL, Barletta JA, Ghossein RA, Juhlin CC, Jung CK, et al. Overview of the 2022 WHO Classification of Thyroid Neoplasms. Endocr Pathol. 2022;33(1):27\u201363.","journal-title":"Endocr Pathol"},{"issue":"4","key":"839_CR2","doi-asserted-by":"publisher","first-page":"188928","DOI":"10.1016\/j.bbcan.2023.188928","volume":"1878","author":"L Zhang","year":"2023","unstructured":"Zhang L, Feng Q, Wang J, Tan Z, Li Q, Ge M. Molecular basis and targeted therapy in thyroid cancer: Progress and opportunities. Biochim Biophys Acta Rev Cancer. 2023;1878(4):188928.","journal-title":"Biochim Biophys Acta Rev Cancer"},{"issue":"4","key":"839_CR3","doi-asserted-by":"publisher","first-page":"101403","DOI":"10.1016\/j.gendis.2024.101403","volume":"12","author":"Z Zou","year":"2025","unstructured":"Zou Z, Zhong L. Anaplastic thyroid cancer: Genetic roles, targeted therapy, and immunotherapy. Genes Dis. 2025;12(4):101403.","journal-title":"Genes Dis"},{"issue":"Suppl 2","key":"839_CR4","doi-asserted-by":"publisher","first-page":"S37","DOI":"10.1038\/modpathol.2008.10","volume":"21","author":"YE Nikiforov","year":"2008","unstructured":"Nikiforov YE. Thyroid carcinoma: molecular pathways and therapeutic targets. Mod Pathol. 2008;21(Suppl 2):S37\u201343.","journal-title":"Mod Pathol"},{"issue":"9","key":"839_CR5","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1016\/j.trecan.2020.05.009","volume":"6","author":"V Subbiah","year":"2020","unstructured":"Subbiah V, Baik C, Kirkwood JM. Clinical Development of BRAF plus MEK Inhibitor Combinations. Trends Cancer. 2020;6(9):797\u2013810.","journal-title":"Trends Cancer"},{"issue":"2","key":"839_CR6","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1007\/s11912-020-01008-4","volume":"23","author":"L Dennison","year":"2021","unstructured":"Dennison L, Mohan AA, Yarchoan M. 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