{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:00:40Z","timestamp":1760238040567,"version":"build-2065373602"},"reference-count":73,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,6,23]],"date-time":"2022-06-23T00:00:00Z","timestamp":1655942400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund (FWF) SFB","doi-asserted-by":"publisher","award":["#F4704-B20","#P32470-B","17015","22028"],"award-info":[{"award-number":["#F4704-B20","#P32470-B","17015","22028"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Medical Scientific Funds of the Mayor of the City of Vienna","award":["#F4704-B20","#P32470-B","17015","22028"],"award-info":[{"award-number":["#F4704-B20","#P32470-B","17015","22028"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>In most patients with advanced systemic mastocytosis (AdvSM), neoplastic mast cells (MC) express KIT D816V. However, despite their disease-modifying potential, KIT D816V-targeting drugs, including midostaurin and avapritinib, may not produce long-term remissions in all patients. Cyclin-dependent kinase (CDK) 4 and CDK6 are promising targets in oncology. We found that shRNA-mediated knockdown of CDK4 and CDK6 results in growth arrest in the KIT D816V+ MC line HMC-1.2. The CDK4\/CDK6 inhibitors palbociclib, ribociclib, and abemaciclib suppressed the proliferation in primary neoplastic MC as well as in all HMC-1 and ROSA cell subclones that were examined. Abemaciclib was also found to block growth in the drug-resistant MC line MCPV-1, whereas no effects were seen with palbociclib and ribociclib. Anti-proliferative drug effects on MC were accompanied by cell cycle arrest. Furthermore, CDK4\/CDK6 inhibitors were found to synergize with the KIT-targeting drugs midostaurin, avapritinib, and nintedanib in inducing growth inhibition and apoptosis in neoplastic MCs. Finally, we found that CDK4\/CDK6 inhibitors induce apoptosis in CD34+\/CD38\u2212 stem cells in AdvSM. Together, CDK4\/CDK6 inhibition is a potent approach to suppress the growth of neoplastic cells in AdvSM. Whether CDK4\/CDK6 inhibitors can improve clinical outcomes in patients with AdvSM remains to be determined in clinical trials.<\/jats:p>","DOI":"10.3390\/cancers14133070","type":"journal-article","created":{"date-parts":[[2022,6,23]],"date-time":"2022-06-23T01:59:47Z","timestamp":1655949587000},"page":"3070","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CDK4\/CDK6 Inhibitors Synergize with Midostaurin, Avapritinib, and Nintedanib in Inducing Growth Inhibition in KIT D816V+ Neoplastic Mast Cells"],"prefix":"10.3390","volume":"14","author":[{"given":"Mathias","family":"Schneeweiss-Gleixner","sequence":"first","affiliation":[{"name":"Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y\u00fcksel","family":"Filik","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriele","family":"Stefanzl","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Berger","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irina","family":"Sadovnik","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karin","family":"Bauer","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dubravka","family":"Smiljkovic","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2735-4645","authenticated-orcid":false,"given":"Gregor","family":"Eisenwort","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadine","family":"Witzeneder","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0917-4117","authenticated-orcid":false,"given":"Georg","family":"Greiner","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"Ihr Labor, Medical Diagnostic Laboratories Vienna, 1220 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7374-4380","authenticated-orcid":false,"given":"Gregor","family":"Hoermann","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"MLL Munich Leukemia Laboratory, 81377 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3555-8672","authenticated-orcid":false,"given":"Ana-Iris","family":"Schiefer","sequence":"additional","affiliation":[{"name":"Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juliana","family":"Schwaab","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, University Medical Center Mannheim and Medical Faculty Mannheim, Heidelberg University, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamad","family":"Jawhar","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, University Medical Center Mannheim and Medical Faculty Mannheim, Heidelberg University, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Reiter","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, University Medical Center Mannheim and Medical Faculty Mannheim, Heidelberg University, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang R.","family":"Sperr","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michel","family":"Arock","sequence":"additional","affiliation":[{"name":"Department of Hematological Biology, Piti\u00e9-Salp\u00eatri\u00e8re Hospital, Pierre et Marie Curie University (UPMC), 75013 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0456-5095","authenticated-orcid":false,"given":"Peter","family":"Valent","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karoline V.","family":"Gleixner","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1111\/1523-1747.ep12468882","article-title":"Classification and diagnosis of mastocytosis: Current status","volume":"96","author":"Metcalfe","year":"1991","journal-title":"J. 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