{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:31:40Z","timestamp":1785407500935,"version":"3.56.0"},"reference-count":41,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","award":["70113307"],"award-info":[{"award-number":["70113307"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"award":["70113307"],"award-info":[{"award-number":["70113307"]}],"id":[{"id":"https:\/\/ror.org\/01wxdd722","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Recurrent genetic and chromosomal aberrations drive multiple myeloma (MM) pathogenesis. Among these, the t(4;14) translocation leads to overexpression of fibroblast growth factor receptor 3 (FGFR3) and is associated with poor prognosis. However, therapeutic approaches directly targeting FGFR3-driven myeloma progression remain limited. Here, we investigated the single-agent activity of ponatinib, a multikinase inhibitor, in MM. KMS18 and U266 myeloma cell lines were treated with ponatinib, and apoptosis induction, as well as VEGF and IL-6 secretion, was assessed. RNA sequencing of MM cells revealed pathway alterations induced by ponatinib treatment, which were subsequently validated by Western blot analysis. In vivo, mice inoculated with 5T33 myeloma cells received ponatinib, and survival was monitored. Notably, ponatinib exerted potent single-agent antimyeloma activity in an FGFR3-dependent manner by inducing apoptosis and suppressing VEGF and IL-6 secretion through inhibition of JAK\/STAT, PI3K\/AKT, and MAPK signaling. In vivo administration prolonged survival in myeloma-bearing mice. Collectively, our findings demonstrate the therapeutic efficacy of ponatinib in FGFR3-expressing MM beyond selective FGFR3 inhibition, suggesting that concurrent suppression of multiple signaling pathways is a critical mechanism of action. These results highlight the therapeutic potential of combined FGFR3-targeted strategies in multiple myeloma and provide a rationale for further clinical investigation.<\/jats:p>","DOI":"10.3390\/ijms27125217","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T06:33:44Z","timestamp":1781073224000},"page":"5217","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of Fibroblast Growth Factor Receptor 3 Signaling by Ponatinib Reduces Growth and Cytokine Production of Multiple Myeloma Cells"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-6630-5295","authenticated-orcid":false,"given":"Sascha","family":"Kampmann","sequence":"first","affiliation":[{"name":"Department of Hematology, Oncology, Stem Cell Transplantation, Immune and Cell Therapy, Clinical Immunology and Rheumatology, University Hospital Bonn, 53127 Bonn, Germany"},{"name":"Center for Integrated Oncology Aachen Bonn Cologne D\u00fcsseldorf (CIO ABCD), 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3239-5444","authenticated-orcid":false,"given":"Sebastian","family":"Schlaweck","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology, Stem Cell Transplantation, Immune and Cell Therapy, Clinical Immunology and Rheumatology, University Hospital Bonn, 53127 Bonn, Germany"},{"name":"Center for Integrated Oncology Aachen Bonn Cologne D\u00fcsseldorf (CIO ABCD), 53127 Bonn, Germany"},{"name":"Mildred Scheel School of Oncology Aachen Bonn Cologne D\u00fcsseldorf (MSSO ABCD), Faculty of Medicine, University Hospital of Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin V.","family":"Becker","sequence":"additional","affiliation":[{"name":"Department of Radiology and Neuroradiology, Bundeswehr Central Hospital, 56072 Koblenz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9416-7455","authenticated-orcid":false,"given":"Chrystel","family":"Flores","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology, Stem Cell Transplantation, Immune and Cell Therapy, Clinical Immunology and Rheumatology, University Hospital Bonn, 53127 Bonn, Germany"},{"name":"Center for Integrated Oncology Aachen Bonn Cologne D\u00fcsseldorf (CIO ABCD), 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annkristin","family":"Heine","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology, Stem Cell Transplantation, Immune and Cell Therapy, Clinical Immunology and Rheumatology, University Hospital Bonn, 53127 Bonn, Germany"},{"name":"Center for Integrated Oncology Aachen Bonn Cologne D\u00fcsseldorf (CIO ABCD), 53127 Bonn, Germany"},{"name":"Division of Hematology, Medical University of Graz, 8036 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Brossart","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology, Stem Cell Transplantation, Immune and Cell Therapy, Clinical Immunology and Rheumatology, University Hospital Bonn, 53127 Bonn, Germany"},{"name":"Center for Integrated Oncology Aachen Bonn Cologne D\u00fcsseldorf (CIO ABCD), 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie A. E.","family":"Held","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology, Stem Cell Transplantation, Immune and Cell Therapy, Clinical Immunology and Rheumatology, University Hospital Bonn, 53127 Bonn, Germany"},{"name":"Center for Integrated Oncology Aachen Bonn Cologne D\u00fcsseldorf (CIO ABCD), 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Banerjee, R., Cicero, K.I., Lee, S.S., and Cowan, A.J. (2023). Definers and drivers of functional high-risk multiple myeloma: Insights from genomic, transcriptomic, and immune profiling. Front. 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