{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T22:52:07Z","timestamp":1788821527545,"version":"build-2803163510"},"reference-count":45,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T00:00:00Z","timestamp":1669766400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Hematological Oncology"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Prevention of fatal side effects during cancer therapy of cancer patients with high\u2010dosed pharmacological inhibitors is to date a major challenge. Moreover, the development of drug resistance poses severe problems for the treatment of patients with leukemia or solid tumors. Particularly drug\u2010mediated dimerization of RAF kinases can be the cause of acquired resistance, also called \u201cparadoxical activation.\u201d In the present work we re\u2010analyzed the effects of different tyrosine kinase inhibitors (TKIs) on the proliferation, metabolic activity, and survival of the Imatinib\u2010resistant,\n                    <jats:italic>KIT<\/jats:italic>\n                    V560G, D816V\u2010expressing human mast cell (MC) leukemia (MCL) cell line HMC\u20101.2. We observed that low concentrations of the TKIs Nilotinib and Ponatinib resulted in enhanced proliferation, suggesting paradoxical activation of the MAPK pathway. Indeed, these TKIs caused BRAF\u2010CRAF dimerization, resulting in ERK1\/2 activation. The combination of Ponatinib with the MEK inhibitor Trametinib, at nanomolar concentrations, effectively suppressed HMC\u20101.2 proliferation, metabolic activity, and induced apoptotic cell death. Effectiveness of this drug combination was recapitulated in the human\n                    <jats:italic>KIT<\/jats:italic>\n                    D816V MC line ROSA\n                    <jats:sup>KIT D816V<\/jats:sup>\n                    and in\n                    <jats:italic>KIT<\/jats:italic>\n                    D816V hematopoietic progenitors obtained from patient\u2010derived induced pluripotent stem cells (iPS cells) and systemic mastocytosis patient samples. In conclusion, mutated KIT\u2010driven Imatinib resistance and possible TKI\u2010induced paradoxical activation can be efficiently overcome by a low concentration Ponatinib and Trametinib co\u2010treatment, potentially reducing the negative side effects associated with MCL therapy.\n                  <\/jats:p>","DOI":"10.1002\/hon.3100","type":"journal-article","created":{"date-parts":[[2022,11,16]],"date-time":"2022-11-16T10:19:45Z","timestamp":1668593985000},"page":"520-534","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Capitalizing on paradoxical activation of the mitogen\u2010activated protein kinase pathway for treatment of Imatinib\u2010resistant mast cell leukemia"],"prefix":"10.1002","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2263-7793","authenticated-orcid":false,"given":"Thomas","family":"Wilhelm","sequence":"first","affiliation":[{"name":"Institute of Biochemistry and Molecular Immunology Medical Faculty RWTH Aachen University  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelo A. S.","family":"Toledo","sequence":"additional","affiliation":[{"name":"Department of Cell Biology Institute for Biomedical Engineering RWTH Aachen University Medical School  Aachen Germany"},{"name":"Helmholtz\u2010Institute for Biomedical Engineering RWTH Aachen University  Aachen Germany"},{"name":"Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation Faculty of Medicine RWTH Aachen University Medical School  Aachen Germany"},{"name":"Center for Integrated Oncology Aachen Bonn Cologne D\u00fcsseldorf (CIO ABCD)  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilka","family":"Simons","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Immunology Medical Faculty RWTH Aachen University  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Stuth","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Immunology 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