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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...

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Main Authors: Schneeweiss-Gleixner, Mathias (Author) , Filik, Yüksel (Author) , Stefanzl, Gabriele (Author) , Berger, Daniela (Author) , Sadovnik, Irina (Author) , Bauer, Karin (Author) , Smiljkovic, Dubravka (Author) , Eisenwort, Gregor (Author) , Witzeneder, Nadine (Author) , Greiner, Georg (Author) , Hoermann, Gregor (Author) , Schiefer, Ana-Iris (Author) , Schwaab, Juliana (Author) , Jawhar, Mohamad (Author) , Reiter, Andreas (Author) , Sperr, Wolfgang R. (Author) , Arock, Michel (Author) , Valent, Peter (Author) , Gleixner, Karoline V. (Author)
Format: Article (Journal)
Language:English
Published: 23 June 2022
In: Cancers
Year: 2022, Volume: 14, Issue: 13, Pages: 1-29
ISSN:2072-6694
DOI:10.3390/cancers14133070
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3390/cancers14133070
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Author Notes: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
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Summary: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.
Item Description:Im Titel ist "+" hochgestellt
Gesehen am 23.08.2022
Physical Description:Online Resource
ISSN:2072-6694
DOI:10.3390/cancers14133070

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