Buchumschlag

CDK4/CDK6 inhibitors synergize with Midostaurin, Avapritinib, and Nintedanib in inducing growth inhibition in KIT D816V+ neoplastic mast cells

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 kin...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Hauptverfasser: Schneeweiss-Gleixner, Mathias (VerfasserIn) , Filik, Yüksel (VerfasserIn) , Stefanzl, Gabriele (VerfasserIn) , Berger, Daniela (VerfasserIn) , Sadovnik, Irina (VerfasserIn) , Bauer, Karin (VerfasserIn) , Smiljkovic, Dubravka (VerfasserIn) , Eisenwort, Gregor (VerfasserIn) , Witzeneder, Nadine (VerfasserIn) , Greiner, Georg (VerfasserIn) , Hoermann, Gregor (VerfasserIn) , Schiefer, Ana-Iris (VerfasserIn) , Schwaab, Juliana (VerfasserIn) , Jawhar, Mohamad (VerfasserIn) , Reiter, Andreas (VerfasserIn) , Sperr, Wolfgang R. (VerfasserIn) , Arock, Michel (VerfasserIn) , Valent, Peter (VerfasserIn) , Gleixner, Karoline V. (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 23 June 2022
In: Cancers
Year: 2022, Jahrgang: 14, Heft: 13, Pages: 1-29
ISSN:2072-6694
DOI:10.3390/cancers14133070
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3390/cancers14133070
Volltext
Verfasserangaben:Mathias Schneeweiss-Gleixner, Yüksel Filik, Gabriele Stefanzl, Daniela Berger, Irina Sadovnik, Karin Bauer, Dubravka Smiljkovic, Gregor Eisenwort, Nadine Witzeneder, Georg Greiner, Gregor Hoermann, Ana-Iris Schiefer, Juliana Schwaab, Mohamad Jawhar, Andreas Reiter, Wolfgang R. Sperr, Michel Arock, Peter Valent and Karoline V. Gleixner
Beschreibung
Zusammenfassung: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- 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.
Beschreibung:Im Titel ist "+" hochgestellt
Gesehen am 23.08.2022
Beschreibung:Online Resource
ISSN:2072-6694
DOI:10.3390/cancers14133070

Ähnliche Einträge