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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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
23 June 2022
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| 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
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| 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 |
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| 245 | 1 | 0 | |a CDK4/CDK6 inhibitors synergize with Midostaurin, Avapritinib, and Nintedanib in inducing growth inhibition in KIT D816V+ neoplastic mast cells |c 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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| 520 | |a 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. | ||
| 650 | 4 | |a abemaciclib | |
| 650 | 4 | |a avapritinib | |
| 650 | 4 | |a CDK4/CDK6 | |
| 650 | 4 | |a drug-combinations | |
| 650 | 4 | |a KIT D816V | |
| 650 | 4 | |a midostaurin | |
| 650 | 4 | |a palbociclib | |
| 650 | 4 | |a ribociclib | |
| 650 | 4 | |a systemic mastocytosis | |
| 650 | 4 | |a targeted therapy | |
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